CN110526914B - Polymorphic substance of ALK inhibitor and preparation method thereof - Google Patents

Polymorphic substance of ALK inhibitor and preparation method thereof Download PDF

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CN110526914B
CN110526914B CN201810520684.6A CN201810520684A CN110526914B CN 110526914 B CN110526914 B CN 110526914B CN 201810520684 A CN201810520684 A CN 201810520684A CN 110526914 B CN110526914 B CN 110526914B
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polymorph
pyrimidine
pyrrolo
piperidin
dimethylamino
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CN110526914A (en
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冀冲
孙德广
杨利民
史建龙
王再全
佟鹤芳
张传玉
王红瑞
李毅
陈岩
杨嘉铭
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Capital Pharmaceutical Holdings Beijing Co ltd
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    • 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
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Abstract

The invention relates to N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxylpolylaminePhenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Polymorphs of pyrimidine-2, 4-diamine and methods for their preparation.

Description

Polymorphic substance of ALK inhibitor and preparation method thereof
Technical Field
The invention relates to an ALK inhibitor polymorphism, in particular to N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Polymorphs of pyrimidine-2, 4-diamine and methods for their preparation.
Background
N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]The pyrimidine-2, 4-diamine is a high-selectivity small-molecule ALK tyrosine kinase inhibitor, has the inhibitory effect on ALK tyrosine kinase at the cellular level with nanomolar effect intensity, has complete inhibitory effect on the tumor growth of non-small cell lung cancer and lymphoma caused by abnormal high expression of ALK fusion protein in animal bodies, and N is2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Pyrimidine-2, 4-diamine resistance to the currently clinically leading same ALK inhibitor crizotinibThe ALK kinase mutant subtype with closely related medicinal properties has a remarkable inhibiting effect, and the structural formula is as follows:
Figure BSA0000164482670000011
the synthetic method of the compound is disclosed in Chinese patent application 201710009761.7, but the crystal form condition of the compound is not involved, and no other literature reports N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]A crystalline form of pyrimidine-2, 4-diamine. The polymorphism of the medicine has important significance on the physical properties, bioavailability, quality and process of the preparation, the difference of physicochemical properties among different crystal forms of the polymorphism medicine influences the stability of the medicine, and the bioavailability may have obvious difference when the same medicine has different crystal forms. Different crystal forms affect the dissolution rate of the drug, and the difference of surface free energy of different crystal forms can cause different bonding force among crystal particles, and affect the fluidity, particle uniformity, content uniformity and physical stability of the drug. Therefore, research on its crystal form is required.
Drawings
Figure 1 is an X-ray powder diffraction pattern of polymorph a.
Figure 2 is an X-ray powder diffraction pattern of polymorph B.
Figure 3 is an X-ray powder diffraction pattern of polymorph C.
Figure 4 is an X-ray powder diffraction pattern of polymorph D.
Figure 5 is an X-ray powder diffraction pattern of polymorph E.
Figure 6 is a DSC profile of polymorph a.
Figure 7 is a DSC profile of polymorph B.
Figure 8 is a DSC profile of polymorph C.
Figure 9 is a DSC profile of polymorph D.
Figure 10 is a TGA profile of polymorph D.
Disclosure of Invention
The invention relates toAnd N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Polymorphic form A, B, C, D, E of pyrimidine-2, 4-diamine and a process for its preparation.
The invention relates to N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Polymorph form A of pyrimidine-2, 4-diamine, crystalline form N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]The pyrimidine-2, 4-diamine has an X-ray powder diffraction pattern as shown in figure 1, the measurement error of 2 theta is +/-0.10 degrees, and a plurality of characteristic peaks between 0 and 50 degrees are shown in table 1.
Table 1: 2 theta Angle and d-value of polymorph A
2 theta angle d- Relative strength
5.002 17.667 100.00
7.113 12.427 31.71
11.151 7.935 49.19
15.416 5.748 30.37
15.816 5.604 26.02
16.046 5.524 44.23
18.091 4.904 12.60
19.028 4.664 38.64
20.167 4.403 12.29
21.526 4.128 13.72
22.734 3.912 10.99
25.422 3.504 32.37
25.927 3.437 15.67
The invention relates to N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Polymorph form B of pyrimidine-2, 4-diamine, crystalline form N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]The pyrimidine-2, 4-diamine has an X-ray powder diffraction pattern as shown in figure 2, the measurement error of 2 theta is +/-0.10 degrees, and a plurality of characteristic peaks between 0 and 50 degrees are shown in table 2.
Table 2: 2 theta Angle and d-value of polymorph B
2 theta angle d- Relative strength
6.951 12.717 100.00
7.101 12.450 63.11
11.915 7.428 47.42
12.222 7.242 34.19
14.416 6.144 17.43
14.797 5.987 24.24
15.186 5.835 94.80
15.457 5.733 10.77
17.285 5.131 10.10
17.566 5.049 44.88
18.197 4.875 32.93
18.670 4.753 46.37
20.178 4.401 53.32
20.602 4.311 31.62
21.077 4.215 54.15
21.568 4.120 22.90
22.135 4.016 10.90
23.124 3.846 22.93
23.820 3.736 23.41
24.578 3.622 34.31
24.912 3.574 22.08
26.532 3.360 20.51
28.150 3.170 13.72
The invention relates to N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Polymorph form C of pyrimidine-2, 4-diamine, crystalline form N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]The pyrimidine-2, 4-diamine has an X-ray powder diffraction pattern as shown in FIG. 3, the measurement error of 2 theta is +/-0.10 degrees, and a plurality of characteristic peaks between 0 and 50 degrees are shown in Table 3.
Table 3: 2 theta Angle and d-value of polymorph C
2θ d-value Relative strength
5.0186 17.60888 100.00
6.5079 13.58204 11.70
9.7245 9.09545 22.34
11.1230 7.95487 17.93
13.1441 6.73585 11.96
15.4008 5.75355 15.89
15.7390 5.63067 28.64
16.0408 5.52541 14.36
18.9815 4.67550 14.01
19.4420 4.56579 16.31
25.3748 3.51013 14.74
The invention relates to N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Polymorph form D of pyrimidine-2, 4-diamine, crystalline form N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropyl) isopropyl alcoholPhenylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]The pyrimidine-2, 4-diamine has an X-ray powder diffraction pattern as shown in FIG. 4, the measurement error of 2 theta is +/-0.10 degrees, and a plurality of characteristic peaks between 0 and 50 degrees are shown in Table 4.
Table 4: 2 theta Angle and D-value of polymorph D
Figure BSA0000164482670000051
Figure BSA0000164482670000061
The invention relates to N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Polymorph form E of pyrimidine-2, 4-diamine, crystalline form N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]The pyrimidine-2, 4-diamine has an X-ray powder diffraction pattern as shown in FIG. 5, and has a measurement error of 2 theta of + -0.10 degrees and a plurality of characteristic peaks between 0 and 50 degrees as shown in Table 5.
Table 5: 2 theta Angle and d-value of polymorph E
Figure BSA0000164482670000062
Figure BSA0000164482670000071
The numerical relative intensities in the seven tables above are defined in the following table:
relative strength Definition of
80-100 VS (very strong)
60-80 S (Strong)
40-60 M (middle)
10-40 W (Weak)
The invention also provides N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Process for the preparation of pyrimidine-2, 4-diamine polymorphs A, B, C, D and E, N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]The pyrimidine-2, 4-diamine is synthesized according to the method of patent Chinese patent application 201710009761.7, and the preparation methods of the five polymorphic forms are all N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]The pyrimidine-2, 4-diamine is recrystallized in different solvents or crystallized by heating in water.
The polymorphic form A is prepared by reacting N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Heating and dissolving the pyrimidine-2, 4-diamine in n-propanol and acetonitrile, and standing for crystallization.
The polymorphic form B is prepared by reacting N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Dissolving pyrimidine-2, 4-diamine in the solvent of diStanding in the hexachloro-oxygen ring for crystallization, wherein the crystal is a dioxane solvate of the compound.
The polymorphic form C is prepared by reacting N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]The polymorphic substance A or the polymorphic substance B of the pyrimidine-2, 4-diamine is heated, stirred and crystallized in water.
The polymorphic form D is prepared by reacting N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Heating and dissolving pyrimidine-2, 4-diamine in n-propanol and acetonitrile, and stirring for crystallization, or heating and dissolving pyrimidine-2, 4-diamine in n-propanol and ethyl acetate, and stirring for crystallization.
The polymorphic substance E is prepared by reacting N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Dissolving pyrimidine-2, 4-diamine in n-propanol, standing for crystallization, and obtaining the crystal as an n-propanol solvate of the compound.
The processes for the preparation of polymorphic forms A, B, C, D and E are followed by crystallization, filtration and vacuum drying to remove solvent or water.
The polymorphic form D can be obtained by recrystallization from N-propanol and acetonitrile, or from N-propanol and ethyl acetate, and the product obtained by recrystallization from two solvent systems is subjected to X-ray powder diffraction pattern analysis, the different numbers of 2 theta angles are less than one third, and both contain the characteristic peaks listed in Table 1, so that the N obtained by recrystallization from two solvent systems is considered2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]The pyrimidine-2, 4-diamine belongs to the same crystal form.
The invention discovers N through experiments2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Pyrimidine-2, 4-diamine exists as polymorphs A, B, C, D and E. The five polymorphs are subjected to a crystal form transformation experiment, and show that the stability of the polymorph D is good, and the stability of other polymorphs is poor.
The present invention will be described in further detail with reference to examples of specific embodiments.
Examples 1, N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Preparation of pyrimidine-2, 4-diamine polymorph A
Reacting compound N at room temperature2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N2- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Adding pyrimidine-2, 4-diamine (50.0g), n-propanol (250mL) and acetonitrile (250mL) into a 1000mL single-neck flask, heating to 85 ℃ at the internal temperature under the protection of nitrogen, adjusting the temperature to 25 ℃ after all solids are dissolved, standing for crystallization, performing suction filtration, and performing vacuum drying at 30 ℃ overnight to obtain 35.0g of white needle-like solid, wherein the yield is as follows: 70.0 percent.
DSC graphs (onset temperature 25 ℃, end temperature 250 ℃, heating rate 10 ℃/min) are shown in FIG. 6.
Example 2, N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Preparation of pyrimidine-2, 4-amine polymorph B
Reacting compound N at room temperature2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Adding pyrimidine-2, 4-diamine (1.05g) and 1, 4-oxohexacyclic ring (15mL) into a 50mL single-neck flask, heating to 75 ℃ at the internal temperature under the protection of nitrogen, reducing the temperature to 25 ℃ after all solids are dissolved, standing for crystallization, performing suction filtration, and performing vacuum drying at 30 ℃ overnight to obtain 0.67g of light yellow granular solid, wherein the yield is as follows: 67.0 percent.
DSC graphs (onset temperature 25 ℃, end temperature 250 ℃, heating rate 10 ℃/min)) are shown in FIG. 7.
Example 3, N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Preparation of pyrimidine-2, 4-diamine polymorph C
Reacting compound N at room temperature2-(4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Polymorph a (250mg), polymorph B (250mg) and purified water (50mL) of pyrimidine-2, 4-diamine were added to a 100mL single-neck flask, heated to an internal temperature of 50 ℃, stirred for 5 days, cooled to room temperature, filtered with suction, and vacuum-dried overnight at 30 ℃ to give 0.4g of a pale yellow solid, yield: 80.0 percent.
DSC graphs (onset temperature 25 ℃, end temperature 250 ℃, heating rate 10 ℃/min) are shown in FIG. 8.
Example 4, N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Preparation of pyrimidine-2, 4-diamine polymorph D
Reacting compound N at room temperature2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Adding pyrimidine-2, 4-diamine (60.0g), n-propanol (300mL) and acetonitrile (300mL) into a 1000mL single-neck flask, heating to 85 ℃ at the internal temperature under the protection of nitrogen, reducing the temperature to 25 ℃ after all solids are dissolved, stirring for crystallization, carrying out suction filtration, and carrying out vacuum drying at 30 ℃ overnight to obtain 47.1g of light yellow needle granular solid, wherein the yield is as follows: 78.5 percent.
DSC graphs (onset temperature 25 ℃, end temperature 250 ℃, heating rate 10 ℃/min) are shown in FIG. 9.
The TGA profile (start temperature 25 deg.C, end temperature 250 deg.C, heating rate 10 deg.C/min) is shown in FIG. 10.
Example 5, N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Preparation of pyrimidine-2, 4-diamine polymorph E
Reacting compound N at room temperature2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Adding pyrimidine-2, 4-diamine (1.0g) and n-propanol (30mL) into a 100mL single-neck flask, heating to an internal temperature of 97 ℃ under the protection of nitrogen, reducing the temperature to 25 ℃ after all solids are dissolved, standing and precipitatingThe crystals were filtered with suction and dried overnight under vacuum at 30 ℃ to give a pale yellow granular solid 0.72g, yield: 72.0 percent.
Example 6, N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Polymorph a and polymorph D of pyrimidine-2, 4-diamine.
Reacting compound N at room temperature2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Polymorph a (500mg), polymorph D (500mg) and purified water (70mL) of pyrimidine-2, 4-diamine were added to a 250mL single-neck flask, heated to an internal temperature of 50 ℃, stirred for 5 days, cooled to room temperature, filtered with suction, and vacuum-dried overnight at 30 ℃ to give 0.8g of a pale yellow solid, yield: 80.0 percent.
The solid above was sent to X-ray powder diffraction and the results indicated the conversion of polymorph a to polymorph D.
Example 7, N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Polymorph C and polymorph D of pyrimidine-2, 4-diamine.
Reacting compound N at room temperature2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N2- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Polymorph C (200mg), polymorph D (200mg) and purified water (50mL) of pyrimidine-2, 4-diamine were added to a 100mL single-neck flask, heated to an internal temperature of 50 ℃, stirred for 5 days, cooled to room temperature, filtered with suction, and vacuum-dried overnight at 30 ℃ to give 0.3g of a pale yellow solid, yield: 75.0 percent.
The solid above was sent to X-ray powder diffraction and the results indicated the conversion of polymorph C to polymorph D.
The results show that the stability of the polymorphic form D is good, and the stability of other forms is poor.

Claims (15)

1.N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Polymorph a of pyrimidine-2, 4-diamine characterised in that it melts at 208 ± 3 ℃ and has an X-ray powder diffraction pattern having characteristic peaks expressed in 2 Θ at: 5.002,7.113, 11.151, 15.417, 15.816, 16.045, 19.028, 25.422.
2. Polymorph a according to claim 1, characterised by an X-ray powder diffraction pattern as shown in figure 1.
3. Process for the preparation of polymorph A according to claim 1 or 2, characterized in that N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Heating and dissolving pyrimidine-2, 4-diamine in n-propanol and acetonitrile, and standing for crystallization to obtain the polymorphic substance A.
4.N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Polymorph B of pyrimidine-2, 4-diamine characterised by an X-ray powder diffraction pattern having characteristic peaks expressed in 2 Θ at: 6.951,7.101, 11.915, 12.222, 15.186, 17.566, 18.670, 20.178, 21.077, 24.578.
5. Polymorph B according to claim 4, characterized by an X-ray powder diffraction pattern as shown in figure 2.
6. Process for the preparation of polymorph B according to claim 4 or 5, characterized in that N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Pyrimidine-2, 4-diamine is dissolved in dioxane under heating, and then is kept stand for crystallization to obtain polymorphic substance B, and nuclear magnetic hydrogen spectrum proves that the polymorphic substance B is a 1: 1 solvate.
7.N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Polymorph C of pyrimidine-2, 4-diamine characterized by an X-ray powder diffraction pattern having characteristic peaks expressed in 2 Θ at the following positions: 5.019,9.725, 11.123, 15.401, 15.739, 18.982, 19.442, 25.375, 25.820.
8. Polymorph C according to claim 7, characterized by an X-ray powder diffraction pattern as shown in figure 3.
9. Process for the preparation of polymorph C according to claim 7 or 8, characterized in that N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Polymorphic substance A and polymorphic substance B of pyrimidine-2, 4-diamine are heated and stirred in water to be crystallized to obtain polymorphic substance C.
10.N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Polymorph D of pyrimidine-2, 4-diamine characterised by an X-ray powder diffraction pattern having characteristic peaks expressed in 2 Θ at: 8.533, 15.779, 16.052, 16.313, 17.114, 17.374, 18.631, 24.171.
11. Polymorph D according to claim 10, characterized by an X-ray powder diffraction pattern as shown in figure 4.
12. Process for the preparation of polymorph D according to claim 10 or 11, characterized in that N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Dissolving pyrimidine-2, 4-diamine in n-propanol and acetonitrile or n-propanol and ethyl acetate, and standing for crystallization to obtain polymorph D.
13.N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (iso)Propylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Polymorph E of pyrimidine-2, 4-diamine characterised by an X-ray powder diffraction pattern having characteristic peaks expressed in 2 Θ at the following positions: 6.355,6.592, 10.836, 11.160, 13.284, 13.672, 15.405, 15.831, 20.328, 23.344, 23.482.
14. Polymorph E according to claim 13, characterized by an X-ray powder diffraction pattern, as shown in figure 5.
15. Process for the preparation of polymorph E according to claim 14, characterized in that N2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenyl) -N4- (2- (isopropylsulfonyl) phenyl) -7H-pyrrolo [2, 3-d]Pyrimidine-2, 4-diamine was dissolved in n-propanol and then crystallized by standing to give polymorph E, which was confirmed to be a 1: 1 solvate by nuclear magnetic hydrogen spectroscopy.
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* Cited by examiner, † Cited by third party
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CN103476776A (en) * 2011-01-07 2013-12-25 北京赛林泰医药技术有限公司 2,4-diamino-6,7-dihydro-5H-pyrrolo[2,3]pyrimidine derivatives as FAK/Pyk2 inhibitors
CN106188060A (en) * 2015-04-29 2016-12-07 厦门大学 Pyrimido azoles, its preparation method, Pharmaceutical composition and application thereof
CN107200741A (en) * 2016-03-16 2017-09-26 北京赛林泰医药技术有限公司 A kind of preparation method of anaplastic lymphoma kinase inhibitor
CN108276410A (en) * 2017-01-06 2018-07-13 北京赛林泰医药技术有限公司 A kind of anaplastic lymphoma kinase inhibitor and its preparation method and application

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103476776A (en) * 2011-01-07 2013-12-25 北京赛林泰医药技术有限公司 2,4-diamino-6,7-dihydro-5H-pyrrolo[2,3]pyrimidine derivatives as FAK/Pyk2 inhibitors
CN106188060A (en) * 2015-04-29 2016-12-07 厦门大学 Pyrimido azoles, its preparation method, Pharmaceutical composition and application thereof
CN107200741A (en) * 2016-03-16 2017-09-26 北京赛林泰医药技术有限公司 A kind of preparation method of anaplastic lymphoma kinase inhibitor
CN108276410A (en) * 2017-01-06 2018-07-13 北京赛林泰医药技术有限公司 A kind of anaplastic lymphoma kinase inhibitor and its preparation method and application

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