CN113024543A - Polymorphic substance of Bcl-2 selective inhibitor salt and preparation method thereof - Google Patents

Polymorphic substance of Bcl-2 selective inhibitor salt and preparation method thereof Download PDF

Info

Publication number
CN113024543A
CN113024543A CN201911248527.5A CN201911248527A CN113024543A CN 113024543 A CN113024543 A CN 113024543A CN 201911248527 A CN201911248527 A CN 201911248527A CN 113024543 A CN113024543 A CN 113024543A
Authority
CN
China
Prior art keywords
methyl
polymorph
dimethyl
oxy
sulfonyl
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
Application number
CN201911248527.5A
Other languages
Chinese (zh)
Inventor
李毅
冀冲
刘玲
史建龙
刘瑶
杨嘉铭
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shouyao Holdings Beijing Co Ltd
Original Assignee
Shouyao Holdings Beijing Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Shouyao Holdings Beijing Co Ltd filed Critical Shouyao Holdings Beijing Co Ltd
Priority to CN201911248527.5A priority Critical patent/CN113024543A/en
Publication of CN113024543A publication Critical patent/CN113024543A/en
Pending legal-status Critical Current

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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 invention relates to a polymorphic substance of Bcl-2 selective inhibitor salt and a preparation method thereof.

Description

Polymorphic substance of Bcl-2 selective inhibitor salt and preparation method thereof
Technical Field
The present invention relates to polymorphs of pharmaceutical compounds, in particular to polymorphs of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride and a process for their preparation.
Background
2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride is a small molecule Bcl-2 inhibitor. Apoptosis plays an important role in ensuring a balance between proliferation and apoptosis of cells of an organism. Disorders of this pathway lead to a variety of diseases. Anti-apoptotic Bcl-2 proteins play an important role in the regulation of apoptosis, and are associated with a number of diseases, and in a variety of cancer and immune system disorders, the overexpression of Bcl-2 proteins is associated with tolerance to chemotherapy, disease progression, and overall prognosis, and there is a need in the therapeutic arts for active compounds that inhibit the anti-apoptotic protein Bcl-2. . The structural formula is as follows:
Figure BSA0000196925950000011
the synthesis method of the compound is disclosed in Chinese patent application No. 201910248251.4, however, no crystalline form of the compound is mentioned and no other literature reports a crystalline form of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride. 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 1X-ray powder diffraction pattern of polymorph a.
Figure 2X-ray powder diffraction pattern of polymorph B.
Figure 3X-ray powder diffraction pattern of polymorph C.
Figure 4. X-ray powder diffraction pattern of polymorph D.
Figure 5. X-ray powder diffraction pattern of polymorph E.
Figure 6. X-ray powder diffraction pattern of polymorph F.
Figure 7X-ray powder diffraction pattern of polymorph G.
Figure 8X-ray powder diffraction pattern of polymorph H.
Figure 9X-ray powder diffraction pattern of polymorph I.
Disclosure of Invention
The present invention relates to 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride A, B, C, D, E, F, G, H, I and a process for its preparation.
The present invention relates to a polymorphic form A of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-2' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 '-diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride in the crystalline form of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4' -chloro-2-yl) oxy '-fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride has an X-ray powder diffraction pattern as shown in FIG. 1, a measurement error of 2 theta of + -0.10 degrees, and contains a plurality of characteristic peaks between 0 and 50 degrees as shown in Table 1.
Table 1: 2 theta Angle and d-value of polymorph A
Figure BSA0000196925950000031
Figure BSA0000196925950000041
Figure BSA0000196925950000051
The present invention relates to a polymorphic form B of 2- ((1H-pyrrolo [2, 3-B ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-2' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 '-diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride, the crystalline form of 2- ((1H-pyrrolo [2, 3-B ] pyridin-5-yl) oxy) -4- (1- ((4' -chloro-2-yl) oxy '-fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride has an X-ray powder diffraction pattern as shown in FIG. 2, a measurement error of 2 theta of + -0.10 degrees, and contains a plurality of characteristic peaks between 0 and 50 degrees as shown in Table 2.
Table 2: 2 theta Angle and d-value of polymorph B
Figure BSA0000196925950000052
Figure BSA0000196925950000061
The present invention relates to polymorph C of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-2' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 '-diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride, the crystalline form of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4' -chloro-2-yl) oxy) '-fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride has an X-ray powder diffraction pattern as shown in FIG. 3, a measurement error of 2 theta of. + -. 0.10 degrees, and contains a plurality of characteristic peaks between 0 and 50 degrees as shown in Table 3.
Table 3: 2 theta Angle and d-value of polymorph C
Figure BSA0000196925950000071
Figure BSA0000196925950000081
Figure BSA0000196925950000091
The present invention relates to polymorph D of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-2' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 '-diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride, the crystalline form of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4' -chloro-2-yl) '-fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride has an X-ray powder diffraction pattern as shown in FIG. 4, a measurement error of 2 theta of. + -. 0.10 degrees, and contains a plurality of characteristic peaks between 0 and 50 degrees as shown in Table 4.
Table 4: 2 theta Angle and D-value of polymorph D
2 theta angle d-value Relative strength
5.667 15.595 100.00
5.986 14.766 14.16
9.013 9.812 12.61
13.654 6.485 11.24
18.109 4.899 15.25
18.961 4.680 12.31
21.222 4.187 13.11
23.014 3.865 17.08
24.292 3.664 11.23
The present invention relates to polymorph E of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-2' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 '-diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride, the crystalline form of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4' -chloro-2-yl) oxy) '-fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride has an X-ray powder diffraction pattern as shown in FIG. 5, a measurement error of 2 theta of. + -. 0.10 degrees, and contains 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
2 theta angle d-value Relative strength
5.767 15.326 100.00
6.849 12.907 16.35
13.985 6.333 13.45
17.386 5.101 13.11
21.194 4.192 17.23
23.088 3.852 16.56
24.831 3.586 13.66
25.693 3.467 11.73
The present invention relates to a polymorphic form F of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-2' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 '-diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride, this crystalline form of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4' -chloro-2-yl) '-fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride has an X-ray powder diffraction pattern as shown in FIG. 6, a measurement error of 2 theta of. + -. 0.10 degrees, and contains a plurality of characteristic peaks between 0 and 50 degrees as shown in Table 6.
Table 6: 2 theta Angle and d-value of polymorph F
2 theta angle d-value Relative strength
6.017 14.689 100.00
9.566 9.246 11.55
11.540 7.668 26.12
14.291 6.198 37.39
14.756 6.004 28.89
15.522 5.709 33.88
17.013 5.212 16.95
18.583 4.775 30.25
19.064 4.656 22.25
20.358 4.362 22.00
21.497 4.134 29.32
22.974 3.871 21.70
24.278 3.666 25.69
25.346 3.514 12.92
26.516 3.362 18.66
27.738 3.216 11.84
28.906 3.089 10.36
The present invention relates to a polymorphic form G of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-2' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 '-diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride, this crystalline form of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4' -chloro-2-yl) '-fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride has an X-ray powder diffraction pattern as shown in FIG. 7, a measurement error of 2 theta of. + -. 0.10 degrees, and contains a plurality of characteristic peaks between 0 and 50 degrees as shown in Table 7.
Table 7: 2 theta Angle and d-value of polymorph G
Figure BSA0000196925950000121
Figure BSA0000196925950000131
The present invention relates to a polymorphic form H of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-2' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 '-diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride, the crystalline form of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4' -chloro-2-yl) oxy '-fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride has an X-ray powder diffraction pattern as shown in FIG. 8, a measurement error of 2 theta of. + -. 0.10 degrees, and contains a plurality of characteristic peaks between 0 and 50 degrees as shown in Table 8.
Table 8: 2 theta Angle and d-value of polymorph H
Figure BSA0000196925950000132
Figure BSA0000196925950000141
The present invention relates to polymorph I of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-2' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 '-diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride in the crystalline form of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4' -chloro-2-yl) oxy '-fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride has an X-ray powder diffraction pattern as shown in FIG. 9, a measurement error of 2 theta of. + -. 0.10 degrees, and contains a plurality of characteristic peaks between 0 and 50 degrees as shown in Table 9.
Table 9: 2 theta Angle and d-value of polymorph I
Figure BSA0000196925950000151
Figure BSA0000196925950000161
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 a process for the preparation of 2- ((1H-pyrrolo [2, 3-B ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride A, B, C, D, E, F, G, H, I, 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 '-chloro-2' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 '-diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride was synthesized according to the method of patent Chinese patent application No. 201910248251.4, and all of the nine polymorphic forms were prepared by reacting 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4' -chloro-pyridin-4-yl) sulfonyl) benzamide hydrochloride -2 '-fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride was recrystallized in different solvents or transcrystallized by heating in water.
Polymorph a is prepared by transcrystallization of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride with stirring in methanol or ethanol at room temperature, or by crystallization in tetrahydrofuran and water.
Polymorph B is prepared by adding 2- ((1H-pyrrolo [2, 3-B ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride to heated methanol and stirring or after dissolving in dimethyl sulfoxide and adding methanol for crystallization.
Polymorph C is prepared by dissolving 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride in ethylene glycol monomethyl ether under heating for static crystallization, or stirring in acetonitrile for crystallization, or standing in N-methylpyrrolidone/acetone/water mixed solvent for crystallization.
Polymorph D is prepared by crystallization of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride in acetone or in a mixed solvent of N, N-dimethylformamide/acetone.
Polymorph E is prepared by crystallization of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride dissolved in tetrahydrofuran, or dissolving in N, N-dimethylformamide/ethyl acetate mixed solvent for crystallization.
Polymorph F is prepared by crystallizing 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride in a mixed solvent of N-methylpyrrolidone/acetonitrile or in a mixed solvent of N, N-dimethylformamide/methanol, or dissolving in N, N-dimethylformamide/acetonitrile mixed solvent for crystallization.
Polymorph G was prepared by crystallization of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride in dichloromethane.
Polymorph H was prepared by quiescently crystallizing 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride dissolved in N-methylpyrrolidone/methanol.
Polymorph I is prepared by static crystallization of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride dissolved in N-methylpyrrolidone/ethyl acetate or stirred crystallization in N-methylpyrrolidone/methyl tert-butyl ether.
The polymorph A, B, C, D, E, F, G, H, I is prepared by crystallization, filtration, and vacuum drying to remove solvent and water.
In the preparation process of the polymorphic form, products obtained by recrystallization by using different solvent systems are analyzed by X-ray powder diffraction pattern and classified, different crystal form characteristic peaks and different numbers of 2 theta angles are less than one third, so that the 2- ((1H-pyrrole [2, 3-b ] pyridine-5-yl) oxygen) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrobenzene obtained by crystallization or crystal transformation of different solvent systems are considered Yl) sulfonyl) benzamide hydrochloride belongs to the same crystal form.
The invention finds through experiments that 2- ((1H-pyrrolo [2, 3-B ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride has polymorphic forms A, B, C, D, E, F, G, H, I. The nine polymorphic substances are subjected to a stability acceleration experiment, and show that the polymorphic substance D has good stability.
The present invention will be described in further detail with reference to examples of specific embodiments.
EXAMPLE 1 preparation of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride polymorph A
The compound 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride (300mg), methanol (6mL) was added to a 10mL one-necked flask, stirred at room temperature for 18 hours, filtered off with suction, dried under vacuum at 25 ℃ overnight, 265mg of an orange solid was obtained, yield: 88.3 percent.
Example 2 preparation of 2, 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride polymorph A
The compound 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride (300mg), ethanol (6mL) was added to a 10mL one-necked flask, stirred at room temperature for 18 hours, filtered off with suction, dried under vacuum at 25 ℃ overnight, 280mg of an orange solid are obtained, yield: 93.3 percent.
EXAMPLE 3 preparation of polymorph A of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride
The compound 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride (200mg), tetrahydrofuran (6mL) and water (6mL) were added to a 10mL one-necked flask, heated to complete dissolution, stirred at room temperature for 3 hours, suction filtered and dried overnight under vacuum at 25 ℃ to give 165mg of an orange solid in yield: 82.5 percent.
Example 4, form a stability study:
two samples of form a prepared in example 1 were placed in an open atmosphere at 25 ℃/60% relative humidity for 60 days, at 40 ℃/75% relative humidity for 44 days and 475 days, respectively, and then sampled for HPLC. The results are shown in Table 10:
table 10: study of stability of Crystal form A
Figure BSA0000196925950000201
Figure BSA0000196925950000211
Example 5 preparation of polymorph B of 2- ((1H-pyrrolo [2, 3-B ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride
The compound 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride polymorph (4.2g) and methanol (50mL) were added to a 100mL one-neck flask, heated to reflux under nitrogen for 15 minutes, cooling to 25 ℃, stirring for crystallization for 1 hour, performing suction filtration, and performing vacuum drying at 25 ℃ overnight to obtain 2.3g of orange granular solid, wherein the yield is as follows: 54.7 percent.
Example 6 preparation of polymorph B of 2- ((1H-pyrrolo [2, 3-B ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride
The compound 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride polymorph (500mg) and dimethylsulfoxide (1mL) were added to a 25mL one-neck flask, stirred until all dissolved, methanol (25mL) was added to precipitate a solid, which was stirred at room temperature for 3 hours, filtered with suction, and dried under vacuum at 25 ℃ overnight to give 57mg of an orange granular solid, yield: 11.4 percent.
Example 7 preparation of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride polymorph C
The compound 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride polymorph (500mg) and N-methylpyrrolidone (1mL) were added to a 25mL one-neck flask, stirred until all dissolved, acetone (10mL) and water (5mL) were added to precipitate a solid, which was left to crystallize at room temperature for 2 days, filtered with suction and dried under vacuum at 25 ℃ overnight to give an orange granular solid 86mg, yield: 17% and the purity is 99.58%.
EXAMPLE 8 preparation of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride polymorph C
The compound 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride polymorph (1g) and acetonitrile (40mL) were added to a 100mL one-neck flask, heated to complete dissolution, left to crystallize at room temperature, suction filtration and vacuum drying at 25 ℃ overnight gave 120mg of an orange granular solid in yield: 12% and purity 97.09%.
Example 9 preparation of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride polymorph C
The compound 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride polymorph (200mg) and ethylene glycol monomethyl ether (6mL) were added to a 10mL one-neck flask, heated until all dissolved, standing at room temperature for crystallization, performing suction filtration, and performing vacuum drying at 25 ℃ overnight to obtain 103mg of an orange granular solid, wherein the yield is as follows: 51.1 percent.
EXAMPLE 10 preparation of polymorph D of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride
The compound 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride polymorph (500mg) and N, N-dimethylformamide (1mL) were added to a 25mL one-neck flask, all dissolved, acetone (10mL) was added, allowed to stand for crystallization, filtered with suction, and vacuum dried at 25 ℃ overnight to give 318mg of an orange granular solid in yield: 63.6 percent and the purity is 99.35 percent.
EXAMPLE 11 preparation of polymorph D of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride
The compound 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride polymorph (300mg) and acetone (6mL) were added to a 10mL one-neck flask, all dissolved, crystallized with stirring at room temperature, suction filtration and vacuum drying at 25 ℃ overnight gave 200mg of an orange granular solid in yield: 66.6 percent and the purity is 99.73 percent.
Example 12, form D stability study:
two samples of form D prepared in example 11 were placed open to the atmosphere at 25 ℃/60% relative humidity for 60 days, 40 ℃/75% relative humidity for 44 days and 475 days, respectively, and then sampled for HPLC. The results are shown in Table 11:
table 11: study of Crystal form D stability
Figure BSA0000196925950000241
The results show that the crystal form D has better stability.
EXAMPLE 13 preparation of polymorph E of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride
The compound 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride polymorph (500mg) and tetrahydrofuran (3mL) were added to a 10mL one-neck flask, all dissolved, crystallized with stirring at room temperature, suction filtered and vacuum dried overnight at 25 ℃ to give 320mg of an orange granular solid in yield: 64.0 percent.
EXAMPLE 14 preparation of polymorph E of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride
The compound 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride polymorph (500mg) and N, N-dimethylformamide (1mL) were added to a 25mL one-neck flask, all dissolved, ethyl acetate (10mL) was added, left to crystallize, filtered with suction, and vacuum dried at 25 ℃ overnight to give 429mg of an orange granular solid, yield: 85.8 percent and the purity is 99.63 percent.
Example 15 preparation of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride polymorph F
The compound 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride polymorph (500mg) and N, N-dimethylformamide (1mL) were added to a 25mL one-neck flask, all dissolved, methanol (10mL) was added, left to crystallize, filtered with suction, and vacuum dried at 25 ℃ overnight to give 323mg of an orange granular solid in yield: 64.6 percent and the purity is 99.71 percent.
Example 16 preparation of polymorphic form F of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride
The compound 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride polymorph (500mg) and N, N-dimethylformamide (1mL) were added to a 25mL one-neck flask, all dissolved, acetonitrile (10mL) was added, stirred for crystallization, filtered with suction, and dried overnight under vacuum at 25 ℃ to give 367mg of an orange granular solid, yield: 73.4 percent and the purity is 99.87 percent.
Example 17 preparation of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride polymorph F
The compound 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride polymorph (500mg) and N-methylpyrrolidone (1mL) were added to a 25mL one-neck flask, all dissolved, acetonitrile (10mL) was added, stirred for crystallization, filtered with suction, and dried under vacuum at 25 ℃ overnight to give an orange granular solid 330mg, yield: 66 percent and the purity is 99.88 percent.
EXAMPLE 18 preparation of polymorph G of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride
The compound 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride polymorph (300mg) and dichloromethane (6mL) were added to a 10mL one-neck flask, stirred until a solid precipitated, filtered with suction, vacuum drying overnight at 25 ℃ gave 183mg of yellow particulate solid in yield: 61.0 percent and the purity is 99.54 percent.
EXAMPLE 19 preparation of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride polymorph H
The compound 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride polymorph (500mg) and N-methylpyrrolidone (1mL) were added to a 25mL one-neck flask, all dissolved, methanol (10mL) was added, allowed to stand for crystallization, filtered with suction, and vacuum dried at 25 ℃ overnight to give 385mg of an orange granular solid in yield: 77.0 percent and the purity is 99.65 percent.
EXAMPLE 20 preparation of polymorph I of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride
The compound 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride polymorph (500mg) and N-methylpyrrolidone (1mL) were added to a 25mL one-neck flask, all dissolved, ethyl acetate (10mL) was added, left to crystallize, filtered with suction, and vacuum dried at 25 ℃ overnight to give 469mg of an orange granular solid in yield: 94.0 percent and the purity is 99.41 percent.
EXAMPLE 21 preparation of polymorph I of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride
The compound 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride polymorph (500mg) and N-methylpyrrolidone (1mL) were added to a 25mL one-neck flask, all dissolved, methyl tert-butyl ether (10mL) was added, stirred to crystallize, filtered and dried overnight under vacuum at 25 ℃ to give 495mg of an orange granular solid in yield: 99.0 percent and the purity is 99.10 percent.

Claims (27)

  1. Polymorph a of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride characterized by an X-ray powder diffraction pattern having characteristic peaks at the following positions expressed in 2 Θ: 5.669,5.964,7.533,7.976,8.222,9.382, 10.506, 10.934, 11.351, 12.061, 12.675, 13.801, 14.565, 15.212, 15.545, 16.605, 17.088, 17.826, 18.211, 19.28, 20.519, 21.753, 22.24, 23.093, 24.282, 25.544, 26.927, 27.426, 28.449, 29.822, 30.09.
  2. 2. Polymorph a according to claim 1, characterised by an X-ray powder diffraction pattern as shown in figure 1.
  3. 3. A process for the preparation of polymorph a according to claim 1 or 2, characterized in that 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride is crystallized in methanol and ethanol or in tetrahydrofuran and water to give polymorph a.
  4. Polymorph B of 2- ((1H-pyrrolo [2, 3-B ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride, characterized by an X-ray powder diffraction pattern with characteristic peaks at the following positions, denoted 2 Θ: 5.185,5.722,7.628, 10.631, 13.92, 15.622, 15.857, 17.284, 17.977, 18.436, 19.969, 20.31, 22.405.
  5. 5. Polymorph B according to claim 4, characterized by an X-ray powder diffraction pattern as shown in figure 2.
  6. 6. A process for the preparation of polymorph B according to claim 4 or 5, characterized in that 2- ((1H-pyrrolo [2, 3-B ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride is crystallized in hot methanol or after dissolution in dimethyl sulfoxide and crystallization is carried out by adding methanol to give polymorph B.
  7. Polymorph C of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride, characterized by an X-ray powder diffraction pattern with characteristic peaks at the following positions expressed in 2 Θ: 6.049,7.949,8.198, 10.311, 10.890, 11.426, 12.126, 13.098, 15.458, 16.466, 16.677, 17.587, 17.943, 18.333, 18.986, 19.555, 19.932, 20.760, 21.332, 22.376, 23.054, 23.524, 24.470, 25.045, 27.030, 29.345.
  8. 8. Polymorph C according to claim 7, characterized by an X-ray powder diffraction pattern as shown in figure 3.
  9. 9. A process for the preparation of polymorph C according to claim 7 or 8, characterized in that 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride is crystallized by standing in ethylene glycol monomethyl ether or by stirring in acetonitrile, or statically crystallizing in a mixed solvent of N-methylpyrrolidone/acetone/water to obtain the polymorphic substance C.
  10. Polymorph D of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride, characterized by an X-ray powder diffraction pattern with characteristic peaks at the following positions expressed in 2 Θ: 5.667,5.986,9.013, 13.654, 18.109, 18.961, 21.222, 23.014.
  11. 11. Polymorph D according to claim 10, characterized by an X-ray powder diffraction pattern as shown in figure 4.
  12. 12. A process for the preparation of polymorph D according to claim 10 or 11, characterized in that 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride is crystallized by stirring in acetone or a mixed N, N-dimethylformamide/acetone solvent to give polymorph D.
  13. 13.2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-
    Polymorph E of yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride characterized by an X-ray powder diffraction pattern having characteristic peaks at the following positions, expressed in 2 Θ: 5.767,6.849, 13.985, 17.386, 21.194, 23.088, 24.831.
  14. 14. Polymorph E according to claim 13, characterized by an X-ray powder diffraction pattern, as shown in figure 5.
  15. 15. A process for the preparation of polymorph E according to claims 13 and 14, characterized in that 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride is crystallized in tetrahydrofuran or an N, N-dimethylformamide/ethyl acetate mixture to give polymorph E.
  16. Polymorph F of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride, characterized by an X-ray powder diffraction pattern with characteristic peaks at the following positions expressed in 2 Θ: 6.017, 11.540, 14.291, 14.756, 15.522, 18.583, 19.064, 21.497, 24.278.
  17. 17. Polymorph F according to claim 16, characterized by an X-ray powder diffraction pattern as shown in figure 6.
  18. 18. A process for the preparation of polymorph F according to claims 16 and 17, characterized in that 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride is crystallized in a mixed solvent of N-methylpyrrolidone/acetonitrile, or dissolving in N, N-dimethylformamide/methanol mixed solvent for crystallization, or dissolving in N, N-dimethylformamide/acetonitrile mixed solvent for crystallization to obtain polymorphic substance F.
  19. 19.2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-
    Polymorph G of the hydrochloride salt of phenyl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide, characterized by an X-ray powder diffraction pattern having characteristic peaks at the following positions, expressed in 2 Θ: 6.310,9.772, 12.742, 17.318, 18.281, 19.622, 20.709.
  20. 20. Polymorph G according to claim 19, characterized by an X-ray powder diffraction pattern as shown in figure 7.
  21. 21. Process for the preparation of polymorph G according to claims 19 and 20, characterized in that 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride is crystallized in dichloromethane to give polymorph G.
  22. Polymorph H of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride, characterized by an X-ray powder diffraction pattern with characteristic peaks at the following positions expressed in 2 Θ: 6.544, 16.819, 18.590, 19.148, 19.699, 20.014, 20.180, 25.893.
  23. 23. Polymorph H according to claim 22, characterized by an X-ray powder diffraction pattern as shown in figure 8.
  24. 24. Process for the preparation of polymorph H according to claims 22 and 23, characterized in that, crystallization of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) 4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride in N-methylpyrrolidone/methanol gave polymorph H.
  25. Polymorph I of 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride, characterized by an X-ray powder diffraction pattern with characteristic peaks at the following positions expressed in 2 Θ: 6.624,7.438,9.519, 13.168, 15.095, 15.917, 17.089, 17.519, 17.679, 18.022, 18.507, 18.980, 19.554, 19.896, 21.724, 23.749, 24.382, 28.055.
  26. 26. Polymorph I according to claim 25, characterized by an X-ray powder diffraction pattern as shown in figure 9.
  27. 27. Process for the preparation of polymorph I according to claims 25 and 26, characterized in that 2- ((1H-pyrrolo [2, 3-b ] pyridin-5-yl) oxy) -4- (1- ((4 ' -chloro-2 ' -fluoro-5, 5-dimethyl-3, 4, 5, 6-dihydro- [1, 1 ' -diphenyl ] -2-yl) methyl) -1, 2, 3, 6-tetrahydropyridin-4-yl) -N- ((4- (((4-fluorotetrahydro-2H-pyran-4-yl) methyl) amino) -3-nitrophenyl) sulfonyl) benzamide hydrochloride is quiescently crystallized in N-methylpyrrolidone/ethyl acetate, or dissolving in N-methyl pyrrolidone/methyl tert-butyl ether, and crystallizing under stirring to obtain polymorph I.
CN201911248527.5A 2019-12-09 2019-12-09 Polymorphic substance of Bcl-2 selective inhibitor salt and preparation method thereof Pending CN113024543A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201911248527.5A CN113024543A (en) 2019-12-09 2019-12-09 Polymorphic substance of Bcl-2 selective inhibitor salt and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201911248527.5A CN113024543A (en) 2019-12-09 2019-12-09 Polymorphic substance of Bcl-2 selective inhibitor salt and preparation method thereof

Publications (1)

Publication Number Publication Date
CN113024543A true CN113024543A (en) 2021-06-25

Family

ID=76450859

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201911248527.5A Pending CN113024543A (en) 2019-12-09 2019-12-09 Polymorphic substance of Bcl-2 selective inhibitor salt and preparation method thereof

Country Status (1)

Country Link
CN (1) CN113024543A (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109293656A (en) * 2017-07-24 2019-02-01 北京赛林泰医药技术有限公司 Bcl-2 selective depressant and its preparation and use
CN111747949A (en) * 2019-03-29 2020-10-09 首药控股(北京)股份有限公司 Bcl-2 selective inhibitors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109293656A (en) * 2017-07-24 2019-02-01 北京赛林泰医药技术有限公司 Bcl-2 selective depressant and its preparation and use
CN111747949A (en) * 2019-03-29 2020-10-09 首药控股(北京)股份有限公司 Bcl-2 selective inhibitors

Similar Documents

Publication Publication Date Title
AU2015330554B2 (en) Crystal form of bisulfate of JAK inhibitor and preparation method therefor
US20180370948A1 (en) P-toluenesulfonate for mek kinase inhibitor, method of preparation thereof, and method of use thereof
AU2015342444B2 (en) Crystalline form of JAK kinase inhibitor bisulfate and a preparation method thereof
EP3176173A1 (en) Crystalline free bases of c-met inhibitor or crystalline acid salts thereof, and preparation methods and uses thereof
US10011591B2 (en) Crystalline form of afatinib dimaleate
JP2023089169A (en) Synthesis method of furoimidazopyridine compound, crystal form of furoimidazopyridine compound, and crystal form of salt thereof
CN108997355A (en) A kind of refining methd of citric acid tropsch imatinib compound
CN108779122B (en) Crystal form of bisulfate of JAK kinase inhibitor and preparation method thereof
EP1951738B1 (en) Further crystalline forms of rostafuroxin
CN107286220B (en) 1,2, 4-triazole coupled dihydromyricetin derivative and preparation method and application thereof
CN107417626B (en) Polymorphic form of 2-aminopyrimidine compound
CN107043368B (en) Crystals of arylamine pyrimidine compounds and salts thereof
CN113024543A (en) Polymorphic substance of Bcl-2 selective inhibitor salt and preparation method thereof
CN110078706B (en) Imatinib derivative and preparation method and application thereof
EP4063361A1 (en) Crystal forms of fused ring compound, and composition thereof, preparation method therefor and application thereof
CN110194741B (en) 4-benzoyl piperazine-3-nitro-1, 8-naphthalimide derivative and preparation method and application thereof
CN110526914B (en) Polymorphic substance of ALK inhibitor and preparation method thereof
CN114989172A (en) Polymorphic substance of tyrosine kinase inhibitor and preparation method thereof
CN110903291B (en) Salt of heteroaryl [4,3-c ] pyrimidine-5-amine derivative, crystal form of salt and preparation method
CN112334473B (en) Crystal form of heteroaryl [4,3-c ] pyrimidine-5-amine derivative and preparation method thereof
US20230121346A1 (en) The salts of a compound and the crystalline forms thereof
KR20120022940A (en) NOVEL STABLE CRYSTAL OF 1-(2'-CYANO-2'-DEOXY-β-D-ARABINOFURANOSYL)CYTOSINE MONOHYDROCHLORIDE
CN113387934B (en) Polyaryl substituted imidazole derivative and preparation method and application thereof
CN110272388B (en) 4-dithioformic acid piperazine-3-nitro-1, 8-naphthalimide derivative and synthesis method and application thereof
CN117003772A (en) Pharmaceutically acceptable salts of heterocyclic compounds, and crystal forms, preparation methods and uses thereof

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
CB02 Change of applicant information
CB02 Change of applicant information

Address after: 100176 915, floor 9, block a, building 1, No. 10, Ronghua Middle Road, Beijing Economic and Technological Development Zone, Beijing

Applicant after: Capital Pharmaceutical Holdings (Beijing) Co.,Ltd.

Address before: 100176 915, floor 9, block a, building 1, No. 10, Ronghua Middle Road, Beijing Economic and Technological Development Zone, Beijing

Applicant before: Shouyao holding (Beijing) Co.,Ltd.

SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination