CN108456210A - A kind of polymorph and preparation method thereof of alk tyrosine kinase inhibitor - Google Patents

A kind of polymorph and preparation method thereof of alk tyrosine kinase inhibitor Download PDF

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Publication number
CN108456210A
CN108456210A CN201710095518.1A CN201710095518A CN108456210A CN 108456210 A CN108456210 A CN 108456210A CN 201710095518 A CN201710095518 A CN 201710095518A CN 108456210 A CN108456210 A CN 108456210A
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China
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polymorph
amine
pyrroles
methylpiperazine
yls
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Inventor
张传玉
***
冀冲
孙德广
张晓军
韩军儒
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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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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 (2 (2 methoxyl group 4 (4 (4 methyl piperazine, the 1 base) piperidinyl-1 base) aniline) 6 of N isopropyls 2,7 dihydro 5H pyrroles [2,3 d] pyrimidine, 4 base amine) benzsulfamide polymorph and preparation method thereof.

Description

A kind of polymorph and preparation method thereof of alk tyrosine kinase inhibitor
Technical field
The present invention relates to the polymorphics of medical compounds, and in particular to N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- Methylpiperazine-1-yl) piperidin-1-yl) aniline) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide Polymorph and preparation method thereof.
Background technology
N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline) -6,7- bis- Hydrogen -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide is that a highly selective small molecule alk tyrosine kinase inhibits Agent has alk tyrosine kinase in cellular level the inhibiting effect of nanomole grade action intensity, in animal body for ALK ( Anaplastic lymphom kinase) tumour growth of non-small cell lung cancer caused by fusion protein overexpression and lymthoma has completely Inhibiting effect, and N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidines -1- bases) aniline) - 6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide is to clinically leading similar ALK inhibitor gram at present Azoles is especially pronounced for the inhibiting effect for the ALK kinase mutant hypotypes that Buddhist nun's drug resistance is closed closely.Structural formula is as follows：
The synthetic method of the compound discloses in WO2012092880, but is not directed to the crystal form situation of compound, and nothing Other document reports N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline) -6, 7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide crystal form.And the polymorphic of drug is to the physical of drug Matter, bioavilability, the quality of preparation and technique are significant, between the different crystal forms of polymorph medicine, physicochemical property The crystal form of the stability of differentia influence drug, same drug is different, and bioavilability might have significant difference.Different crystalline substances Type influences the dissolution rate of drug, also, the difference of different crystal forms surface free energy, can cause the combination between crystalline particle Power is different, influences mobility, granulation uniformity, uniformity of dosage units and the physical stability of drug.Therefore, it is necessary to its crystal form into Row research.
Description of the drawings
Fig. 1 is the X-ray powder diffraction figure of crystal form A.
Fig. 2 is the X-ray powder diffraction figure of crystal form B.
Fig. 3 is the X-ray powder diffraction figure of crystal form C.
Fig. 4 is the X-ray powder diffraction figure of crystal form D.
Fig. 5 is the X-ray powder diffraction figure of crystal form E.
Fig. 6 is the X-ray powder diffraction figure of crystal form F.
Fig. 7 is the X-ray powder diffraction figure of crystal form G.
Fig. 8 is differential scanning calorimetry (DSC) figure of crystal form A.
Fig. 9 is differential scanning calorimetry (DSC) figure of crystal form B.
Figure 10 is differential scanning calorimetry (DSC) figure of crystal form C.
Figure 11 is differential scanning calorimetry (DSC) figure of crystal form D.
Figure 12 is differential scanning calorimetry (DSC) figure of crystal form E.
Figure 13 is differential scanning calorimetry (DSC) figure of crystal form F.
Figure 14 is differential scanning calorimetry (DSC) figure of crystal form G.
Invention content
The present invention relates to N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidines -1- bases) benzene Amine) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide polymorph A, B, C, D, E, F, G and its system Preparation Method.
The present invention relates to N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidines -1- bases) benzene Amine) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide polymorphic A, crystal type N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline) -6,7- dihydro -5H- pyrroles [2,3-d] is phonetic Pyridine -4- bases amine) benzsulfamide have X ray powder diffractions as shown in Figure 1, measurement error ± 0.10 degree of 2 θ, 0 It is as shown in table 1 containing multiple characteristic peaks between~50 degree.
Table 1：The d- values of polymorphic A and 2 angles θ
d- 2 angles θ Relative intensity
17.62 5.015 36.6
9.15 9.671 27.57
8.25 10.727 17.69
7.65 11.565 25.90
6.34 13.976 24.79
5.87 15.087 30.91
5.40 16.419 35.99
5.31 16.687 44.76
4.78 18.570 55.97
4.09 21.747 100.00
3.66 24.332 44.00
The present invention relates to N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidines -1- bases) benzene Amine) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide polymorph b, crystal type N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline) -6,7- dihydro -5H- pyrroles [2,3-d] is phonetic Pyridine -4- bases amine) benzsulfamide have X ray powder diffractions as shown in Figure 2, measurement error ± 0.10 degree of 2 θ, 0 It is as shown in table 2 containing multiple characteristic peaks between~50 degree.
Table 2：The d- values of polymorph b and 2 angles θ
The present invention relates to N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidines -1- bases) benzene Amine) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide polymorphic C, crystal type N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline) -6,7- dihydro -5H- pyrroles [2,3-d] is phonetic Pyridine -4- bases amine) benzsulfamide have X ray powder diffractions as shown in Figure 3, measurement error ± 0.10 degree of 2 θ, 0 It is as shown in table 3 containing multiple characteristic peaks between~50 degree.
Table 3：The d- values of polymorphic C and 2 angles θ
d- 2 angles θ Relative intensity
18.58 4.755 100.00
9.28 9.531 21.41
8.83 10.014 25.67
8.51 10.390 32.43
6.18 14.325 55.67
4.60 19.287 18.26
3.71 24.008 14.87
The present invention relates to N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidines -1- bases) benzene Amine) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide polymorphic D, crystal type N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline) -6,7- dihydro -5H- pyrroles [2,3-d] is phonetic Pyridine -4- bases amine) benzsulfamide have X ray powder diffractions as shown in Figure 4, measurement error ± 0.10 degree of 2 θ, 0 It is as shown in table 4 containing multiple characteristic peaks between~50 degree.
Table 4：The d- values of polymorphic D and 2 angles θ
The present invention relates to N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidines -1- bases) benzene Amine) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide polymorphic E, crystal type N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline) -6,7- dihydro -5H- pyrroles [2,3-d] is phonetic Pyridine -4- bases amine) benzsulfamide have X ray powder diffractions as shown in Figure 5, measurement error ± 0.10 degree of 2 θ, 0 It is as shown in table 5 containing multiple characteristic peaks between~50 degree.
Table 5：The d- values of polymorphic E and 2 angles θ
d- 2 angles θ Relative intensity
19.19 4.857 100.00
8.86 9.73 21.60
8.33 10.614 25.54
6.78 14.622 35.69
5.81 15.249 27.59
The present invention relates to N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidines -1- bases) benzene Amine) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide polymorphic F, crystal type N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline) -6,7- dihydro -5H- pyrroles [2,3-d] is phonetic Pyridine -4- bases amine) benzsulfamide have X ray powder diffractions as shown in FIG. 6, measurement error ± 0.10 degree of 2 θ, 0 It is as shown in table 6 containing multiple characteristic peaks between~50 degree.
Table 6：The d- values of polymorphic F and 2 angles θ
The present invention relates to N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidines -1- bases) benzene Amine) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide polymorphic G, crystal type N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline) -6,7- dihydro -5H- pyrroles [2,3-d] is phonetic Pyridine -4- bases amine) benzsulfamide have X ray powder diffractions as shown in Figure 7, measurement error ± 0.10 degree of 2 θ, 0 It is as shown in table 7 containing multiple characteristic peaks between~50 degree.
Table 7：The d- values of polymorphic G and 2 angles θ
d- 2 angles θ Relative intensity
18.09 4.884 100.00
8.88 9.962 56.11
8.27 10.701 57.17
6.76 13.098 20.44
6.53 13.558 14.68
6.36 13.929 17.03
6.00 14.755 20.26
5.76 15.382 31.28
5.43 16.325 24.97
4.35 20.432 18.53
4.14 21.449 15.67
4.06 21.876 26.29
3.84 23.143 23.63
3.53 25.245 33.23
Umerical relative intensity according to the form below definition in above-mentioned seven tables：
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 N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidines -1- Base) aniline) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) and benzsulfamide polymorphic A, B, C, D, E, F, G preparation Method, N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline) -6,7- dihydros - 5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide synthesizes gained according to patent WO2012092880 methods, and it is described more than seven kinds The preparation method of crystal form is by N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (the 4- methyl of chromatography column separating purification Piperazine -1- bases) piperidin-1-yl) aniline) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide is different molten It is recrystallized in agent, the N- isopropyls -2- (2- (2- methoxyl group -4- (4- that eluent when chromatography is concentrated to give (4- methylpiperazine-1-yls) piperidin-1-yl) aniline) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzene sulfonyl Amine, purity 99.21% are yellow solid.
The preparation method of polymorphic A is by N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperazines Pyridine -1- bases) aniline) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide is dissolved in N, N- dimethyl formyls Amine and acetonitrile, n,N-Dimethylformamide and acetone, n,N-Dimethylformamide and isopropanol, n,N-Dimethylformamide, second One or two kinds of in the mixed solvents of glycol monomethyl ether and water, filter, at room temperature stirring and crystallizing while hot.
The preparation method of polymorph b is by N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperazines Pyridine -1- bases) aniline) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide is dissolved in trifluoroethanol, while hot It filters, after poor solvent ethanol is added dropwise at 40~60 DEG C, stirring and crystallizing at room temperature.
The preparation method of polymorphic C is by N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperazines Pyridine -1- bases) aniline) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide is dissolved in trifluoroethanol, while hot It filters, after isopropanol is added dropwise at 40~60 DEG C, stirring and crystallizing at room temperature.
The preparation method of polymorphic D is by N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperazines Pyridine -1- bases) aniline) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide is dissolved in trifluoroethanol, while hot It filters, after distilled water is added dropwise at 40~60 DEG C, stirring and crystallizing at room temperature.
The preparation method of polymorphic E is by N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) Piperidin-1-yl) aniline) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide is dissolved in ethylene glycol list first Ether filters while hot, after ethyl alcohol is added dropwise at 90~100 DEG C, stirring and crystallizing at room temperature.
The preparation method of polymorphic F is by N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) Piperidin-1-yl) aniline) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide is dissolved in ethylene glycol list first Ether filters while hot, at room temperature stirring and crystallizing.
The preparation method of polymorphic G is by N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperazines Pyridine -1- bases) aniline) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide is dissolved in dichlormethyl ether and methanol In the mixed solvent, filter while hot, at room temperature stirring and crystallizing.
The polymorph A, B, C, D, E are filtered after crystallization in the preparation method of F, G, and be dried in vacuo remove solvent and Moisture.
Above-mentioned polymorphic A can be by n,N-Dimethylformamide and acetonitrile, n,N-Dimethylformamide and acetone, N, N- bis- Methylformamide and isopropanol, one or two kinds of in the mixed solvent weights of n,N-Dimethylformamide, glycol monoethyl ether and water Crystallization obtains, and carries out X-ray powder diffraction figure analysis to the product that different solvents system is recrystallized to give, 2 angles θ difference numbers are small In one third, and all comprising characteristic peak listed in table 1, it is thus regarded that the N- isopropyls that three kinds of solvent systems are recrystallized to give Base -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline) -6,7- dihydro -5H- pyrroles [2,3- D] pyrimidine-4-yl amine) benzsulfamide belongs to same crystal form.
N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methyl piperazine -1- bases) piperazines are found through experiments that in the present invention Pyridine -1- bases) aniline) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) and benzsulfamide there are polymorph A, B, C, D, E, F, G.Seven kinds of polymorphs are recrystallized to give in different solvents, to seven kinds of polymorphs be placed on 25 ± 2 DEG C, Study on the stability is carried out under the conditions of relative humidity 60 ± 10%, display polymorph A has good stability, and other several polymorphics Object stability is poor.
Embodiment With reference to embodiment is described in further details the present invention.
Analysis method is as follows：
It is filler (Welch Ultimate XB-phenyl 250*4.6,3 μm) chromatographic column with phenyl bonded silica, With 0.3% triethylamine (formic acid tune pH4.2) for mobile phase A, with methanol-acetonitrile=40: 60 be Mobile phase B, and according to the form below carries out ladder Degree elution, Detection wavelength 251nm, 30 DEG C of column temperature.Area normalization method calculates HPLC purity.
Embodiment 1, N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidines -1- bases) benzene Amine) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide polymorph A preparation
By compound N-isopropyl -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) benzene Amine) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide (2.0g, 3.15 mmol) and N, N- dimethyl methyl Amide (10mL) is added in the three-necked flask of 50mL, is heated to 100~105 DEG C, solid all dissolves, and filters while hot, filtrate It is added in the three-necked flask of 100mL, is heated to 100 DEG C, isopropanol (30mL) is added dropwise, after being added dropwise, stirring analysis at room temperature Crystalline substance, filtering, 45 DEG C are dried in vacuum overnight, and obtain yellow solid 1.57g, yield：78.5%.
HPLC tests purity 99.28%.
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 2, N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidines -1- bases) benzene Amine) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide polymorph b preparation
By compound N-isopropyl -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) benzene Amine) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide (2.0g, 3.15 mmol) and trifluoroethanol (10mL) is added in the three-necked flask of 50mL, is heated to flowing back, and solid all dissolves, and filters while hot, filtrate is added to 100mL Three-necked flask in, be heated to 40~60 DEG C, ethyl alcohol (20mL) be added dropwise, after being added dropwise, stirring and crystallizing, filters, 45 at room temperature It DEG C is dried in vacuum overnight, obtains yellow solid 1.72g, yield：86.0%.
HPLC tests purity 99.31%.
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 9.
Embodiment 3, N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidines -1- bases) benzene Amine) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide polymorph C preparation
By compound N-isopropyl -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) benzene Amine) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide (2.0g, 3.15 mmol) and trifluoroethanol (10mL) is added in the three-necked flask of 50mL, is heated to flowing back, and solid all dissolves, and filters while hot, filtrate is added to 100mL Three-necked flask in, be heated to 40~60 DEG C, isopropanol (20mL) be added dropwise, after being added dropwise, stirring and crystallizing, filters at room temperature, 45 DEG C are dried in vacuum overnight, and obtain yellow solid 1.75g, yield：87.5%.
HPLC tests purity 99.23%.
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 10.
Embodiment 4, N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidines -1- bases) benzene Amine) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide polymorph D preparation
By compound N-isopropyl -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) benzene Amine) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide (2.0g, 3.15 mmol) and trifluoroethanol (10mL) is added in the three-necked flask of 50mL, is heated to flowing back, and solid all dissolves, and filters while hot, filtrate is added to 100mL Three-necked flask in, be heated to 40~60 DEG C, distilled water (30mL) be added dropwise, after being added dropwise, stirring and crystallizing, filters at room temperature, 45 DEG C are dried in vacuum overnight, and obtain yellow solid 1.86g, yield：93.0%.
HPLC tests purity 99.16%.
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 11.
Embodiment 5, N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidines -1- bases) benzene Amine) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide polymorph E preparation
By compound N-isopropyl -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) benzene Amine) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide (2.0g, 3.15 mmol) and glycol monoethyl ether (10mL) is added in the three-necked flask of 50mL, is heated to 100~105 DEG C, and solid all dissolves, and filters while hot, and filtrate is added Into the three-necked flask of 100mL, it is heated to 100 DEG C, ethyl alcohol (20mL) is added dropwise, after being added dropwise, stirring and crystallizing at room temperature, mistake Filter, 45 DEG C are dried in vacuum overnight, and obtain yellow solid 1.88g, yield：94.0%.
HPLC tests purity 99.28%.
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 12.
Embodiment 6, N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidines -1- bases) benzene Amine) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide polymorph F preparation
By compound N-isopropyl -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) benzene Amine) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide (2.0g, 3.15 mmol) and glycol monoethyl ether (10mL) is added in the three-necked flask of 50mL, is heated to 100~105 DEG C, and solid all dissolves, and filters while hot, and filtrate is added Into the three-necked flask of 50mL, stirring and crystallizing, is filtered at room temperature, and 45 DEG C are dried in vacuum overnight, and obtain yellow solid 1.82g, is received Rate：91.0%.
HPLC tests purity 99.34%.
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 13.
Embodiment 7, N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidines -1- bases) benzene Amine) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide polymorph G preparation
Compound CT-707 (2.0g, 3.15mmol), dichloromethane and methanol are added in the three-necked flask of 50 mL, 40 DEG C are heated to, solid all dissolves, and filters while hot, filtrate is added in the three-necked flask of 50mL, at room temperature stirring and crystallizing, mistake Filter, 45 DEG C are dried in vacuum overnight, and obtain yellow solid 1.63g, yield：81.5%.
HPLC tests purity 99.16%.
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 14.
Embodiment 8, N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidines -1- bases) benzene Amine) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide polymorph A, B, C, D, E, F, G stability It investigates.
By the polymorph A, B, C, D, E, F, G that are prepared by Examples 1 to 7 25 ± 2 DEG C, relative humidity 60 ± Study on the stability is carried out under the conditions of 10%, purity result of variations is as follows：
The stability of polymorphic A
Time (moon) Purity
0 99.28%
6 99.25%
12 99.29%
24 99.24%
The stability of polymorph b
Time (moon) Purity
0 99.31%
6 99.26%
12 99.15%
24 98.97%
The stability of polymorphic C
Time (moon) Purity
0 99.23%
6 99.19%
12 99.05%
24 98.97%
The stability of polymorphic D
Time (moon) Purity
0 99.16%
6 99.17%
12 99.04%
24 98.93%
The stability of polymorphic E
The stability of polymorphic F
Time (moon) Purity
0 99.34%
6 99.35%
12 99.15%
24 99.05%
The stability of polymorphic G
Time (moon) Purity
0 99.16%
6 99.10%
12 99.02%
24 98.89%
The above result shows that long-term 24 of polymorphic A has good stability, other several stability of crystal form are poor.

Claims (22)

1.N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline) -6,7- dihydros - 5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide polymorph A, which is characterized in that it is melted at 233 ± 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：5.015,9.671,10.727,11.565,13.976,15.087,16.419,18.570,21.747, 24.332。
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 N- isopropyls -2- (2- (2- methoxyl groups - 4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzene sulphur Amide is in n,N-Dimethylformamide, n,N-Dimethylformamide and isopropanol, n,N-Dimethylformamide and acetone, N, N- bis- Methylformamide and one or two kinds of in the mixed solvents of acetonitrile, glycol monoethyl ether and water are recrystallized to give polymorph A.
5.N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline) -6,7- dihydros - 5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide polymorph b, which is characterized in that X-ray powder diffraction figure is with 2 There is characteristic peak in the following position that θ is indicated：4.804,9.977,10.542,14.517,16.078,21.211,22.279, 24.531。
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 N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzene sulfonyl Amine is recrystallized to give polymorph b in trifluoroethanol and alcohol mixed solvent.
8.N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline) -6,7- dihydros - 5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide polymorph C, which is characterized in that X-ray powder diffraction figure is with 2 There is characteristic peak in the following position that θ is indicated：4.755,9.531,10.014,10.390,14.325,19.287,24.008.
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 N- isopropyls -2- (2- (2- methoxyl groups - 4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzene sulphur Amide is recrystallized to give polymorph C in the in the mixed solvent of trifluoroethanol and isopropanol.
11.N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline) -6,7- bis- Hydrogen -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide polymorph D, which is characterized in that X-ray powder diffraction figure exists There is characteristic peak with the following position that 2 θ are indicated：4.84,9.978,10.625,13.056,15.274,16.185,17.330, 17.697,18.065,19.281,20.055,21.117,22.700,24.887.
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 N- isopropyls -2- (2- (2- methoxies Base -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) Benzsulfamide is recrystallized to give polymorph D in the in the mixed solvent of trifluoroethanol and water.
14.N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline) -6,7- bis- Hydrogen -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide polymorph E, which is characterized in that X-ray powder diffraction figure exists There is characteristic peak with the following position that 2 θ are indicated：4.857,9.73,10.614,14.622,15.249.
15. polymorph E according to claim 14, which is characterized in that X-ray powder diffraction figure, as shown in Figure 5.
16. the preparation method of the polymorph E of claims 14 or 15, which is characterized in that N- isopropyls -2- (2- (2- methoxies Base -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) Benzsulfamide is recrystallized to give polymorph E in the in the mixed solvent of glycol monoethyl ether and ethyl alcohol.
17.N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline) -6,7- bis- Hydrogen -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide polymorph F, which is characterized in that X-ray powder diffraction figure exists There is characteristic peak with the following position that 2 θ are indicated：4.81,9.873,10.255,10.560,13.825,14.521,15.149, 16.073,17.701,18.029,19.770,21.158,21.308,22.443,23.489,24.641,25.139,25.756.
18. polymorph F according to claim 17, which is characterized in that X-ray powder diffraction figure, as shown in Figure 6.
19. the preparation method of the polymorph F of claim 17 or 18, which is characterized in that N- isopropyls -2- (2- (2- methoxies Base -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) Benzsulfamide is recrystallized to give polymorph F in glycol monoethyl ether solvent.
20.N- isopropyls -2- (2- (2- methoxyl groups -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline) -6,7- bis- Hydrogen -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) benzsulfamide polymorph G, which is characterized in that X-ray powder diffraction figure exists There is characteristic peak with the following position that 2 θ are indicated：4.884,9.962,10.701,13.098,13.558,13.929,14.755, 15.382,16.325,20.432,21.449,21.876,23.143,25.245.
21. polymorph G according to claim 20, which is characterized in that X-ray powder diffraction figure, as shown in Figure 7.
22. the preparation method of the polymorph G of claim 20 or 21, which is characterized in that N- isopropyls -2- (2- (2- methoxies Base -4- (4- (4- methylpiperazine-1-yls) piperidin-1-yl) aniline) -6,7- dihydro -5H- pyrroles [2,3-d] pyrimidine-4-yl amine) Benzsulfamide is recrystallized to give polymorph G in the in the mixed solvent of dichloromethane and methanol.
CN201710095518.1A 2017-02-22 2017-02-22 A kind of polymorph and preparation method thereof of alk tyrosine kinase inhibitor Pending CN108456210A (en)

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