CN116813624A - Crystal form of JAK2 inhibitor and preparation method thereof - Google Patents
Crystal form of JAK2 inhibitor and preparation method thereof Download PDFInfo
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- 239000013078 crystal Substances 0.000 title abstract description 27
- 238000002360 preparation method Methods 0.000 title abstract description 22
- 229940121730 Janus kinase 2 inhibitor Drugs 0.000 title description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims abstract description 40
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 20
- -1 phenyl-pyrrolo [2,3-d ] pyrimidine dihydrochloride Chemical compound 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 12
- 230000008569 process Effects 0.000 claims abstract description 8
- 238000002425 crystallisation Methods 0.000 claims abstract description 6
- 230000008025 crystallization Effects 0.000 claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 69
- 150000001875 compounds Chemical class 0.000 claims description 57
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 45
- 239000002904 solvent Substances 0.000 claims description 33
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 238000010438 heat treatment Methods 0.000 claims description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- HVPMMTIMEHDCTN-UHFFFAOYSA-N 2-phenyl-7h-pyrrolo[2,3-d]pyrimidine Chemical compound N1=C2NC=CC2=CN=C1C1=CC=CC=C1 HVPMMTIMEHDCTN-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- 239000012296 anti-solvent Substances 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000010009 beating Methods 0.000 claims description 3
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 claims description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 abstract description 6
- 238000000746 purification Methods 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 12
- 238000002411 thermogravimetry Methods 0.000 description 12
- 238000012360 testing method Methods 0.000 description 11
- 239000012458 free base Substances 0.000 description 10
- 238000004090 dissolution Methods 0.000 description 9
- 238000001228 spectrum Methods 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- 239000003814 drug Substances 0.000 description 6
- 239000012046 mixed solvent Substances 0.000 description 6
- 230000035699 permeability Effects 0.000 description 6
- 239000003513 alkali Substances 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- 238000010586 diagram Methods 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 3
- 150000001860 citric acid derivatives Chemical class 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 230000004580 weight loss Effects 0.000 description 3
- 239000008351 acetate buffer Substances 0.000 description 2
- 239000012736 aqueous medium Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- YKGMKSIHIVVYKY-UHFFFAOYSA-N dabrafenib mesylate Chemical compound CS(O)(=O)=O.S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 YKGMKSIHIVVYKY-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 150000003891 oxalate salts Chemical class 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 2
- 229910017488 Cu K Inorganic materials 0.000 description 1
- 229910017541 Cu-K Inorganic materials 0.000 description 1
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 1
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 1
- 230000005260 alpha ray Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000013097 stability assessment Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
Classifications
-
- 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 invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a A, B, C, D crystal form of 2- { N- [4- (4-methyl) piperazine ] phenyl } amino-5, 6-dihydro-7- [3- (N-tertiary butyl) sulfamido ] phenyl-pyrrolo [2,3-d ] pyrimidine dihydrochloride and a preparation method thereof. The A, B, C, D four crystal forms can be prepared under various different conditions, the crystallization process has good purification effect, and the preparation method of the crystal forms is simple, has low cost, and can obtain 2- { N- [4- (4-methyl) piperazine ] phenyl } amino-5, 6-dihydro-7- [3- (N-tertiary butyl) sulfamido ] phenyl-pyrrolo [2,3-d ] pyrimidine dihydrochloride with high purity, good solubility and good stability.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a A, B, C, D crystal form of 2- { N- [4- (4-methyl) piperazine ] phenyl } amino-5, 6-dihydro-7- [3- (N-tertiary butyl) sulfamido ] phenyl-pyrrolo [2,3-d ] pyrimidine dihydrochloride and a preparation method thereof.
Background
CN110305140a describes a compound 2- { N- [4- (4-methyl) piperazine ] phenyl } amino-5, 6-dihydro-7- [3- (N-t-butyl) sulfamido ] phenyl-pyrrolo [2,3-d ] pyrimidine, which exhibits a highly selective JAK2 inhibitory effect as the free base.
In view of the importance of the solid pharmaceutical forms and the stability thereof in clinical treatment, the compound 2- { N- [4- (4-methyl) piperazine ] phenyl } amino-5, 6-dihydro-7- [3- (N-tert-butyl) sulfamido ] phenyl-pyrrolo [2,3-d ] pyrimidine dihydrochloride is further studied in depth, and the method has important significance for developing medicaments which are suitable for industrial production and have good biological activity.
Disclosure of Invention
The present inventors have long made efforts to solve the problems of solubility in water, oral bioavailability, etc. of the compound 2- { N- [4- (4-methyl) piperazine ] phenyl } amino-5, 6-dihydro-7- [3- (N-tert-butyl) sulfamido ] phenyl-pyrrolo [2,3-d ] pyrimidine, and have found that the preparation of 2- { N- [4- (4-methyl) piperazine ] phenyl } amino-5, 6-dihydro-7- [3- (N-tert-butyl) sulfamido ] phenyl-pyrrolo [2,3-d ] pyrimidine into the corresponding pharmaceutically acceptable salts.
The present invention provides, in the first place, a pharmaceutically acceptable salt of 2- { N- [4- (4-methyl) piperazine ] phenyl } amino-5, 6-dihydro-7- [3- (N-t-butyl) sulfamido ] phenyl-pyrrolo [2,3-d ] pyrimidine, wherein the pharmaceutically acceptable salt is a conventional inorganic salt or an organic salt in the art. In order to improve the physicochemical or biological properties of the medicine, compared with the free alkali (the invention does not particularly indicate, the free alkali refers to 2- { N- [4- (4-methyl) piperazine ] phenyl } amino-5, 6-dihydro-7- [3- (N-tertiary butyl) sulfamido ] phenyl-pyrrolo [2,3-d ] pyrimidine), the invention can realize faster dissolution and release in vivo, is favorable for the absorption and the exertion of the medicine effect of the human body, and has more clinical advantages, and further, the inorganic salt is preferably dihydrochloride, sulfate, phosphate and nitrate; the organic salt is preferably mesylate, citrate, oxalate or succinate. Particularly preferred pharmaceutically acceptable salts are dihydrochloride salts, which have advantages over the free base and other salts in terms of solubility, stability and hygroscopicity.
The invention further provides a A, B, C, D crystal form of 2- { N- [4- (4-methyl) piperazine ] phenyl } amino-5, 6-dihydro-7- [3- (N-tertiary butyl) sulfamido ] phenyl-pyrrolo [2,3-d ] pyrimidine dihydrochloride and a preparation method thereof.
Crystalline form a of compound 2- { N- [4- (4-methyl) piperazine ] phenyl } amino-5, 6-dihydro-7- [3- (N-tert-butyl) sulfamido ] phenyl-pyrrolo [2,3-d ] pyrimidine dihydrochloride of formula (1), having characteristic peaks in the X-ray powder diffraction pattern at 2Θ of 5.989, 8.478, 12.288, 13.315, 16.985, 17.476;
further, the X-ray powder diffraction pattern of the A crystal form has characteristic peaks at diffraction angles 2 theta of 3.105, 5.989, 8.478, 12.288, 13.315, 16.985, 17.476, 22.174 and 24.898.
Further, the X-ray powder diffraction pattern of form a has characteristic peaks at diffraction angles 2θ of 3.105, 5.989, 6.765, 8.478, 12.288, 13.315, 16.432, 16.985, 17.476, 19.370, 22.174, 24.166, 24.898, 30.243.
The present invention also provides a process for preparing form a of a compound of formula (1), the process comprising:
(a) The compound of formula (1) is added into a solvent (I), and the solvent (I) is at least one selected from water, ethanol, methanol, isopropanol, glycol, acetone, methyl tertiary butyl ether, ethyl acetate, acetonitrile, tetrahydrofuran and dioxane, preferably methanol, ethanol and ethanol/water, and is dissolved by stirring or heated to be dissolved or pulped by heating. The volume (ml) of the solvent (I) is 1-60 times of the weight (g) of the compound.
(b) Stirring and crystallizing.
(c) And heating and drying at 40-100deg.C, preferably 50-90deg.C.
The present invention provides an X-ray powder diffraction pattern of form B, B of the compound of formula (1), having characteristic peaks at diffraction angles 2θ of 5.106, 12.765, 17.879, 22.419, 24.214.
Further, the X-ray powder diffraction pattern of the B crystal form has characteristic peaks at diffraction angles 2θ of 3.452, 5.106, 5.762, 6.339, 6.911, 8.900, 11.270, 12.765, 13.914, 17.347, 20.542, 22.419, 24.214.
Further, the X-ray powder diffraction pattern of form B has characteristic peaks at diffraction angles 2θ of 3.452, 5.106, 5.762, 5.957, 6.339, 6.911, 8.900, 10.406, 11.270, 11.924, 12.765, 13.914, 14.247, 17.347, 18.476, 20.542, 22.419, 24.214.
The present invention also provides a process for preparing form B of a compound of formula (1), comprising:
(a) The compound of formula (1) is added to a solvent (II) selected from at least one of water, ethanol, methanol, isopropanol, methyl tert-butyl ether, preferably methanol, ethanol/water, methanol/methyl tert-butyl ether, and dissolved with stirring or heated. The volume (ml) of the solvent (II) is 1-60 times of the weight (g) of the compound
(b) Stirring and crystallizing.
(c) And heating and drying at 10-40 deg.c, preferably 25-40 deg.c.
The present invention provides an X-ray powder diffraction pattern of crystalline form C, C of the compound of formula (1), having characteristic peaks at diffraction angles 2θ of 5.743, 11.931, 13.097, 15.625, 17.066, 18.429.
Further, the X-ray powder diffraction pattern of the C-crystal form has characteristic peaks at diffraction angles 2θ of 5.743, 6.262, 11.931, 12.561, 13.097, 13.967, 15.625, 17.066, 18.429, 18.882, 21.432, 24.496, 24.931.
Further, the X-ray powder diffraction pattern of the C-crystal form has characteristic peaks at diffraction angles 2θ of 5.743, 6.262, 6.551, 11.931, 12.561, 13.097, 13.967, 15.625, 17.066, 18.429, 18.882, 19.180, 19.639, 21.432, 23.133, 24.496, 24.931.
The present invention also provides a process for preparing form C of the compound of formula (1), comprising:
(a) Adding a compound of formula (1) to a solvent (IIIa), beating at room temperature or under heating, wherein the solvent (IIIa) is at least one selected from ethanol, ethylene glycol and acetone, preferably ethanol; or adding the compound of formula (1) to a solvent (IIIb), stirring to dissolve or heating to dissolve, wherein the solvent (IIIb) is selected from at least one of methanol and ethyl acetate or isopropyl acetate or butyl acetate, preferably methanol/ethyl acetate. The volume (ml) of the solvent (III) is 1 to 60 times the weight (g) of the compound.
(b) Stirring and crystallizing.
(c) And heating and drying at 10-40 deg.c, preferably 25-40 deg.c.
The invention provides an X-ray powder diffraction pattern of the crystal form D, D of the compound of the formula (1), wherein the diffraction angles 2 theta are 6.733, 8.670, 11.931, 18.213 and 19.043, and characteristic peaks are formed.
Further, the X-ray powder diffraction pattern of the D crystal form has characteristic peaks at diffraction angles 2 theta of 6.733, 8.670, 11.931, 12.363, 18.213, 19.043, 23.033 and 24.813.
The present invention also provides a process for preparing form D of the compound of formula (1), comprising:
(a) Adding the compound shown in the formula (1) into a solvent (IV), stirring and dissolving or heating and dissolving, dropwise adding an anti-solvent for crystallization, wherein the solvent (IV) is one selected from methanol, ethanol, glycol and water, and preferably methanol. The antisolvent is selected from acetonitrile. The volume ratio of the solvent (IV) to acetonitrile is 2:1-1:10, preferably 1:3, 1:4 or 1:5.
(b) And heating and drying at 20-80 deg.c, preferably 25-50 deg.c.
It should be appreciated that slightly different melting point readings may be given with different types of equipment or with different test conditions. The correct values for the melting points of the different crystal forms will be affected by the purity of the compound, the weight of the sample, the heating rate, the particle size and the checksum maintenance of the test equipment. The numerical values provided cannot be taken as absolute values.
It should be appreciated that slightly different patterns and peaks of XPRD may be given with different types of equipment or with different test conditions. The spectra, peaks and relative intensities of the various crystalline forms will be affected by the purity of the compound, the pretreatment of the sample, the scanning speed, the particle size and the checksum maintenance of the test equipment. The numerical values provided cannot be taken as absolute values.
The X-ray powder diffraction pattern or XPRD of the invention is obtained by Cu-K alpha ray diffraction.
The differential scanning calorimetric analysis or DSC refers to measuring the temperature difference and the heat flow difference between a sample and a reference object in the process of heating or constant temperature of the sample so as to represent all physical changes and chemical changes related to thermal effects and obtain phase change information of the sample.
The diffraction angle 2 theta is a Bragg angle, the unit is degree, and the error range of the 2 theta is +/-0.2.
The invention has the beneficial effects that: the A, B, C, D crystal form of the compound of the formula (1) provided by the invention has the advantages of stability, solubility and preparation dissolution, is more suitable for drug development, meets the requirements of bioavailability and drug effect, can meet the requirements of production, transportation and storage of medicines, has a stable, repeatable and controllable production process, and can be suitable for industrial production.
The A, B, C, D four crystal forms can be prepared under various different conditions, the crystallization process has good purification effect, and the preparation method of the crystal forms is simple, has low cost, and can obtain 2- { N- [4- (4-methyl) piperazine ] phenyl } amino-5, 6-dihydro-7- [3- (N-tertiary butyl) sulfamido ] phenyl-pyrrolo [2,3-d ] pyrimidine dihydrochloride with high purity, good solubility and good stability.
Drawings
FIG. 1 XPRD diagram of form A of a compound of formula (1);
FIG. 2 is a DSC chart of form A of the compound of formula (1);
FIG. 3 is a TGA spectrum of form A of the compound of formula (1);
FIG. 4 XPRD diagram of form B of the compound of formula (1);
FIG. 5 DSC of form B of the compound of formula (1);
FIG. 6 is a TGA spectrum of form B of the compound of formula (1);
FIG. 7 XPRD diagram of form C of the compound of formula (1);
FIG. 8 DSC chart of form C of the compound of formula (1);
FIG. 9 TGA spectrum of form C of the compound of formula (1);
FIG. 10 XPRD diagram of form D of a compound of formula (1);
FIG. 11 is a DSC chart of form D of the compound of formula (1);
figure 12 TGA profile of form D of the compound of formula (1).
Detailed Description
The present invention is further described in detail below with reference to examples, but is not limited thereto.
Test conditions of the instrument used for the experiment:
XRPD is X-ray powder diffraction detection: the measurement is carried out by using a Bruker D8 type X-ray diffractometer according to the rule 0451 of four parts of the edition 2020 of Chinese pharmacopoeia, and the test conditions are as follows: target: cu;40kv, 40mA.
DSC is differential scanning calorimeter: the measurement is carried out by using a TA Q2000 differential scanning calorimeter according to the rule 0661 of the fourth edition of the Chinese pharmacopoeia 2020, and the test conditions are as follows: DSC:30 ℃ 10 ℃/min 300 ℃; TGA:30 ℃ 10 ℃/min 350 ℃.
Example 12 related Properties of pharmaceutically acceptable salts of- { N- [4- (4-methyl) piperazine ] phenyl } amino-5, 6-dihydro-7- [3- (N-t-butyl) sulfamido ] phenyl-pyrrolo [2,3-d ] pyrimidine
1. Melting point
TABLE 1
| Salt type | Melting point | Decomposition temperature |
| Sulfate salt | / | 258.05℃ |
| Dihydrochloride salt | / | 271.44℃ |
| Oxalate salt | 155.10℃ | 230℃ |
| Methanesulfonate salt | 164.22℃ | 225℃ |
| Citrate salt | 135.39℃ | 187.5℃ |
2. Solubility of
The test results show that the solubility of sulfate, dihydrochloride, oxalate, mesylate and citrate in water is improved relative to that of the free base, and the solubility of the free base can be obviously improved by the sulfate and dihydrochloride.
TABLE 2 saturation solubility (in water) test of different salts
3. Stability of
Stability studies of the free base and five different kinds of pharmaceutically acceptable salts thereof under both conditions.
To compare the solid state stability of the five salt forms with that of the free base, stability evaluations were performed for the free base and its dihydrochloride, sulfate, mesylate, oxalate, citrate at 30 ℃ ± 2 ℃/65% rh ± 5% rh and 40 ℃ ± 2 ℃/75% rh ± 5% rh, respectively, for one month. Stability test samples were assayed for purity by HPLC to evaluate chemical stability (HPLC method calculated using area normalization method).
Table 3: summary of stability assessment
Conclusion: the dihydrochloride has no obvious purity reduction under the stable placing condition of 30+/-2 ℃/65%RH+/-5%RH and 40+/-2 ℃/75%RH+/-5%RH, and the free alkali and the sulfate, the methanesulfonate, the oxalate and the citrate thereof have purity reduction to a certain extent under the same placing condition.
4. Moisture absorption assessment
Referring to the guiding principle of the drug hygroscopicity test of the 2020 edition of Chinese pharmacopoeia, the hygroscopicity evaluation is carried out on free alkali and five salt forms thereof. The change in data after 24 hours of storage of the mass of the solid samples (free base and dihydrochloride, sulfate, oxalate, mesylate, citrate) was collected at a constant temperature of 25 ℃ and a relative humidity of 80%, and the summary of the hygroscopicity evaluation is shown in table 4:
table 4: summary of hygroscopicity assessment
| Salt type | Weight gain after moisture absorption | Moisture permeability |
| Sulfate salt | 8.2％ | Has moisture permeability |
| Dihydrochloride salt | 4.5％ | Has moisture permeability |
| Oxalate salt | 7.6％ | Has moisture permeability |
| Methanesulfonate salt | 7.8％ | Has moisture permeability |
| Citrate salt | 4.5％ | Has moisture permeability |
| Free base | 1.7％ | Slightly moisture-absorbing property |
Conclusion: from the above wet-permeability evaluation results, it can be seen that the free base appears slightly wet-permeability, and that all of the five salt forms have wet-permeability, whereas the dihydrochloride salt and the citrate salt have relatively lower wet-permeability, showing better physicochemical properties.
EXAMPLE 22 preparation of crystalline form of- { N- [4- (4-methyl) piperazine ] phenyl } amino-5, 6-dihydro-7- [3- (N-tert-butyl) sulfamido ] phenyl-pyrrolo [2,3-d ] pyrimidine dihydrochloride
1. Preparation of form A
The compound (42 g) of the formula (1) is added into 420ml of absolute ethyl alcohol and 63ml of purified water to obtain a mixed solvent, the mixed solvent is heated, stirred and dissolved, stirred and crystallized, filtered, a filter cake is collected, and the product is obtained by vacuum drying at 80 ℃ (40 g, yield 95%).
The XRPD spectrum of the crystal form A is shown in figure 1 after X-ray powder diffraction, the characteristic peak positions are shown in the following table 5, an endothermic peak exists at 273.68 ℃ in a DSC spectrum, and the weight loss is 2.854% between 25 ℃ and 100 ℃ in thermogravimetric analysis (TGA).
Table 5 characteristic peaks of crystalline form a
2. Preparation of form A
The compound (0.3 g) of the formula (1) is added into 9ml of absolute ethanol, heated, stirred and beaten, stirred and devitrified, filtered, and a filter cake is collected, and the product (0.23 g, yield 77%) is obtained by vacuum drying at 90 ℃, and is detected as a crystal form A by XPRD.
3. Preparation of form A
The compound (0.5 g) of the formula (1) is added into 3ml of absolute methanol, heated, stirred, dissolved, stirred, crystallized, filtered, a filter cake is collected, and the product (0.21 g, yield 42%) is obtained by vacuum drying at 60 ℃, and is detected as a crystal form A by XPRD.
4. Preparation of form B
The compound (3.66 g) of the formula (1) was added to 73ml of absolute ethanol and 4.5ml of purified water to obtain a mixed solvent, the mixed solvent was heated and stirred to dissolve, stirred for crystallization, filtration, and a cake was collected and dried under vacuum at 40℃to obtain a product (3.02 g, yield 82.5%).
The XRPD pattern of the crystal form B is shown in figure 4, the characteristic peak positions are shown in the following table 6, an endothermic peak is arranged at 266.04 ℃ in the DSC spectrum, and the weight loss is 6.505% between 25 ℃ and 100 ℃ in thermogravimetric analysis (TGA).
Table 6B characteristic peaks of crystalline form
5. Preparation of form B
The compound (0.5 g) of the formula (1) is added into 3ml of absolute methanol, heated, stirred, dissolved, stirred, crystallized, filtered, a filter cake is collected, and the product (0.26 g, yield 52%) is obtained by vacuum drying at 30 ℃, and is detected as a crystal form B by XPRD.
6. Preparation of form B
The compound (0.3 g) of the formula (1) is added into a mixed solvent of 9.5ml of anhydrous methanol and 4ml of methyl tertiary butyl ether, the mixture is heated, stirred and dissolved, stirred and crystallized, filtered, a filter cake is collected, and the product (0.21 g, yield 70%) is obtained by vacuum drying at 25 ℃, and is detected to be crystal form B by XPRD.
7. Preparation of form C
The compound (0.3 g) of the formula (1) was added to 9ml of absolute ethanol, heated, stirred and beaten, stirred and devitrified, filtered, and the filter cake was collected and dried under vacuum at 30℃to give the product (0.25 g, yield 83%).
The XRPD pattern of the crystal form C is shown in figure 7, the characteristic peak positions are shown in the following table 7, an endothermic peak exists at 274.4 ℃ in the DSC spectrum, and the weight loss is 7.307% between 25 ℃ and 100 ℃ in thermogravimetric analysis (TGA).
Table 7C characteristic peaks of crystalline form
8. Preparation of form C
The compound (0.3 g) of the formula (1) is added into a mixed solvent of 7ml of anhydrous methanol and 2.8ml of ethyl acetate, the mixture is heated, stirred and dissolved, stirred and crystallized, filtered, a filter cake is collected, and the filter cake is dried in vacuum at 40 ℃ to obtain a product (0.26 g, yield 87%) which is detected as a crystal form C by XPRD.
9. Preparation of form D
The compound of formula (1) (0.3 g) was added to 4ml of anhydrous methanol, dissolved by stirring, 16ml of acetonitrile was added dropwise, stirred for crystallization, filtered, and the cake was collected and dried under vacuum at 30℃to give the product (0.17 g, yield 57%).
The XRPD pattern of the crystal form D is shown in figure 10, the characteristic peak positions are shown in the following table 8, an endothermic peak is arranged at 234.85 ℃ in the DSC spectrum, and the thermogravimetric analysis (TGA) loses weight by 6.25% at 25-100 ℃.
Table 8D characteristic peaks of crystalline form
Example 3 stability test of form A, form B, form C, form D
The purity detection is carried out according to the method 0512 of the fourth edition of the Chinese pharmacopoeia 2015.
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Example 4 influence factor test of form A
The purity detection is carried out according to the method 0512 of the fourth edition of the Chinese pharmacopoeia 2015.
Example 5 solubility determination of form A, form B, form C, form D
According to four-part example solubility test method of Chinese pharmacopoeia 2015, placing the product in a solvent with a certain volume at 25+ -2deg.C, each time
The dissolution was observed within 30 minutes by vigorous shaking for 30 seconds at 5 minutes intervals, and the results were as follows:
EXAMPLE 6 dissolution Properties of crystalline dihydrochloride form in formulation
The in vitro dissolution test can objectively reflect the characteristics of the preparation, and has important guiding and predicting effects on the dissolution and release of the medicine in vivo. The finished product of the dihydrochloride crystal form A preparation can reach more than 85 percent of dissolution rate in 15 minutes in a pH1.2 hydrochloric acid medium, a pH4.5 acetate buffer solution, a pH6.8 phosphate buffer solution (containing 0.05 percent SDS) and an aqueous medium which simulate in-vivo environment by adopting the same prescription and powder direct compression process, so as to realize the quick release effect. The dissolution rate of the finished product of the free alkali preparation in a hydrochloric acid medium with the pH value of 1.2 and an acetate buffer with the pH value of 4.5 can only reach more than 80 percent in 120min, and the dissolution effect of a phosphate buffer with the pH value of 6.8 (containing 0.05 percent of SDS) and an aqueous medium is poorer, and the dissolution rate in 120min is not more than 20 percent.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.
Claims (13)
1. A crystalline form a of compound 2- { N- [4- (4-methyl) piperazine ] phenyl } amino-5, 6-dihydro-7- [3- (N-tert-butyl) sulfamido ] phenyl-pyrrolo [2,3-d ] pyrimidine dihydrochloride of formula (1), characterized by an X-ray powder diffraction pattern having characteristic peaks at 2Θ of 5.989, 8.478, 12.288, 13.315, 16.985, 17.476; preferably, there are characteristic peaks at 2 theta of 3.105, 5.989, 8.478, 12.288, 13.315, 16.985, 17.476, 22.174, 24.898; preferably, there are characteristic peaks at 2 theta of 3.105, 5.989, 6.765, 8.478, 12.288, 13.315, 16.432, 16.985, 17.476, 19.370, 22.174, 24.166, 24.898, 30.243;
2. a process for preparing form a of claim 1, comprising:
(a) Adding a compound of formula (1) into a solvent (I), stirring and dissolving or heating and beating, wherein the solvent (I) is at least one of water, ethanol, methanol, isopropanol, ethylene glycol, acetone, methyl tertiary butyl ether, ethyl acetate, acetonitrile, tetrahydrofuran and dioxane;
(b) Stirring and crystallizing;
(c) Heating and drying at 40-100 deg.c.
3. The process according to claim 2, wherein in step (a) the solvent (i) is selected from methanol, ethanol/water, said solvent (i) being used in a volume (ml) of 1 to 60 times the weight (g) of the compound of formula (1); the temperature of the step (c) is 50-90 ℃.
4. Form B of the compound 2- { N- [4- (4-methyl) piperazine ] phenyl } amino-5, 6-dihydro-7- [3- (N-tert-butyl) sulfamido ] phenyl-pyrrolo [2,3-d ] pyrimidine dihydrochloride of formula (1), characterized by the characteristic peaks in the X-ray powder diffraction pattern at 2Θ of 5.106, 12.765, 17.879, 22.419, 24.214; preferably, there are characteristic peaks at 2 theta of 3.452, 5.106, 5.762, 6.339, 6.911, 8.900, 11.270, 12.765, 13.914, 17.347, 20.542, 22.419, 24.214; preferably, there are characteristic peaks at 2θ of 3.452, 5.106, 5.762, 5.957, 6.339, 6.911, 8.900, 10.406, 11.270, 11.924, 12.765, 13.914, 14.247, 17.347, 18.476, 20.542, 22.419, 24.214.
5. A process for preparing form B of claim 4 comprising:
(a) Adding a compound of formula (1) into a solvent (II), stirring and dissolving or heating and dissolving, wherein the solvent (II) is at least one selected from water, ethanol, methanol, isopropanol and methyl tertiary butyl ether;
(b) Stirring and crystallizing;
(c) Heating and drying at 10-40 deg.c.
6. The process according to claim 5, wherein in step (a) solvent (II) is selected from the group consisting of methanol, ethanol/water, methanol/methyl tert-butyl ether, said solvent (II) being used in a volume (ml) of 1 to 60 times the weight (g) of the compound of formula (1); the temperature of the step (c) is 25-40 ℃.
7. A crystalline form C of compound 2- { N- [4- (4-methyl) piperazine ] phenyl } amino-5, 6-dihydro-7- [3- (N-t-butyl) sulfamido ] phenyl-pyrrolo [2,3-d ] pyrimidine dihydrochloride of formula (1), characterized by an X-ray powder diffraction pattern having characteristic peaks at 2Θ of 5.743, 11.931, 13.097, 15.625, 17.066, 18.429; preferably, there are characteristic peaks at 2θ of 5.743, 6.262, 11.931, 12.561, 13.097, 13.967, 15.625, 17.066, 18.429, 18.882, 21.432, 24.496, 24.931; preferably, there are characteristic peaks at 2θ of 5.743, 6.262, 6.551, 11.931, 12.561, 13.097, 13.967, 15.625, 17.066, 18.429, 18.882, 19.180, 19.639, 21.432, 23.133, 24.496, 24.931.
8. A process for preparing form C of claim 7, comprising:
(a) Adding a compound of formula (1) into a solvent (IIIa), beating at room temperature or under heating, wherein the solvent (IIIa) is at least one selected from ethanol, ethylene glycol and acetone; or adding the compound of formula (1) into a solvent (IIIb), stirring and dissolving or heating and dissolving, wherein the solvent (IIIb) is at least one selected from methanol and ethyl acetate or isopropyl acetate or butyl acetate.
(b) Stirring and crystallizing;
(c) Heating and drying at 10-40 deg.c.
9. The process according to claim 8, wherein in step (a) the solvent (III) is selected from ethanol, methanol/ethyl acetate, the volume (ml) used of said solvent (III) being 1 to 60 times the weight (g) of the compound of formula (1); the temperature of the step (c) is 25-40 ℃.
10. A crystalline form D of compound 2- { N- [4- (4-methyl) piperazine ] phenyl } amino-5, 6-dihydro-7- [3- (N-t-butyl) sulfamido ] phenyl-pyrrolo [2,3-D ] pyrimidine dihydrochloride of formula (1), characterized by an X-ray powder diffraction pattern having characteristic peaks at 2Θ of 6.733, 8.670, 11.931, 18.213, 19.043; preferably, there are characteristic peaks at 2θ of 6.733, 8.670, 11.931, 12.363, 18.213, 19.043, 23.033, 24.813.
11. A process for preparing form D of claim 10, comprising:
(a) Adding a compound of the formula (1) into a solvent (IV), stirring and dissolving or heating and dissolving, and dropwise adding an anti-solvent for crystallization, wherein the solvent (IV) is at least one of methanol, ethanol, glycol and water; the volume ratio of the solvent (IV) to the antisolvent is 2:1-1:10;
(b) Heating and drying at 20-80 deg.c; the volume ratio of the solvent (IV) to the antisolvent in the step (a) is 1:3, 1:4 or 1:5; step (a) solvent (IV) is selected from methanol, and anti-solvent is selected from acetonitrile; the temperature in the step (b) is 25-50 ℃.
12. A salt of the compound 2- { N- [4- (4-methyl) piperazine ] phenyl } amino-5, 6-dihydro-7- [3- (N-tert-butyl) sulphonamido ] phenyl-pyrrolo [2,3-d ] pyrimidine, characterized in that said salt is selected from the group consisting of hydrochloride, sulfate, phosphate, nitrate, mesylate, citrate, oxalate, and succinate.
13. A salt of the compound 2- { N- [4- (4-methyl) piperazine ] phenyl } amino-5, 6-dihydro-7- [3- (N-tert-butyl) sulfamido ] phenyl-pyrrolo [2,3-d ] pyrimidine, as claimed in claim 12, wherein the salt is a dihydrochloride.
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