CN106065016A - A kind of crystal form of cyclin dependent kinase inhibitor and preparation method thereof - Google Patents
A kind of crystal form of cyclin dependent kinase inhibitor and preparation method thereof Download PDFInfo
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- 239000013078 crystal Substances 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 239000002875 cyclin dependent kinase inhibitor Substances 0.000 title abstract description 4
- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 title abstract description 4
- 229940126074 CDK kinase inhibitor Drugs 0.000 title abstract description 3
- 102100034770 Cyclin-dependent kinase inhibitor 3 Human genes 0.000 title abstract description 3
- 101000945639 Homo sapiens Cyclin-dependent kinase inhibitor 3 Proteins 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 238000002425 crystallisation Methods 0.000 claims abstract description 22
- 230000008025 crystallization Effects 0.000 claims abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 102000013701 Cyclin-Dependent Kinase 4 Human genes 0.000 claims abstract description 6
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 claims abstract description 6
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 6
- 239000000126 substance Substances 0.000 claims abstract description 5
- 102000003903 Cyclin-dependent kinases Human genes 0.000 claims abstract description 4
- 108090000266 Cyclin-dependent kinases Proteins 0.000 claims abstract description 4
- 238000011282 treatment Methods 0.000 claims abstract description 4
- 150000002576 ketones Chemical class 0.000 claims abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 238000001228 spectrum Methods 0.000 claims description 7
- 206010006187 Breast cancer Diseases 0.000 claims description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 201000008275 breast carcinoma Diseases 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910002483 Cu Ka Inorganic materials 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 235000010755 mineral Nutrition 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 230000005855 radiation Effects 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 1
- 150000007529 inorganic bases Chemical class 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 4
- 238000001953 recrystallisation Methods 0.000 abstract description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 abstract 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 abstract 1
- WJJMNDUMQPNECX-UHFFFAOYSA-N dipicolinic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=N1 WJJMNDUMQPNECX-UHFFFAOYSA-N 0.000 abstract 1
- 231100000053 low toxicity Toxicity 0.000 abstract 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- 150000003053 piperidines Chemical class 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- WDHAAJIGSXNPFO-UHFFFAOYSA-N 8h-pyrido[2,3-d]pyrimidin-7-one Chemical compound N1=CN=C2NC(=O)C=CC2=C1 WDHAAJIGSXNPFO-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000022131 cell cycle Effects 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 238000000227 grinding Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108091007914 CDKs Proteins 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000011278 mitosis Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 101100223811 Caenorhabditis elegans dsc-1 gene Proteins 0.000 description 1
- 229910017488 Cu K Inorganic materials 0.000 description 1
- 229910017541 Cu-K Inorganic materials 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000005260 alpha ray Effects 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 208000030270 breast disease Diseases 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 229940127554 medical product Drugs 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000011125 single therapy Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The present invention relates to crystal form of a kind of cyclin dependent kinase inhibitor and preparation method thereof.Specifically, I type crystallization that the present invention relates to a kind of cyclin dependent kinase (CDK4&6) inhibitor and preparation method thereof.Specifically; the present invention relates to 6 acetyl group 8 cyclopenta 5 methyl 2 ((5 (piperidines 4 base) pyridine 2 base) amino) pyridos [2; 3 d] the I type crystallization and preparation method thereof of pyrimidine 7 (8H) ketone (formula (I) compound), described crystallization has X ray powder diffraction as shown in Figure 1.Obtained by the present invention, the I type crystallization of formula (I) compound possesses good chemical stability and stability of crystal form, and recrystallisation solvent low toxicity and low residue used, can be preferably applied to clinical treatment.
Description
Technical field
The present invention relates to 6-acetyl group-8-cyclopenta-5-methyl-2-((5-(piperidin-4-yl) pyridine-2-base)
Amino) pyrido [2,3-d] pyrimidine-7 (8H)-one and I crystal thereof.The method according to the invention preparation obtains
Formula (I) compound obtained can be used for the treatment of breast carcinoma.
Background technology
Breast carcinoma is one of modal malignant tumor of women, has sickness rate high, has much aggressive,
But course advancement is slow, Chinese population association has issued " China on February 1st, 2010 in Beijing
Mastopathy investigation report ", report display, the mortality rate of China's urban area breast carcinoma increases
38.91%, breast carcinoma has become as and WomanHealth is threatened maximum disease, is grinding and is listing at present
Breast cancer medicines at least 156 kinds, wherein 68% is target therapeutic agent, numerous studies find
Tumor is relevant to cell cycle abnormality, in tumor cell the mass mutation of mitosis signal protein and
Resisting mitosis signal protein defect causes Proliferative Disorders；All there is genome in major part tumor simultaneously
Unstability (GIN) and chromosome set unstability (CIN), the cell cycle defects that these three is basic
All directly or indirectly caused by the out of control of CDKs.Cyclin dependent kinase (CDK,
Cyclin Dependent Kinase) inhibitor is increasingly becoming popular target.
The a generation secondary CDK inhibitor of exploitation at present is a lot, and secondary medicine of greatest concern includes
The CDK4&6 inhibitor PD-0332991 of Pfizer company and Onyx company joint development, it leads to
Cross the activity of suppression CDK4&6, the phosphorylation of suppression Rb, make E2F-Rb complex be detained
In endochylema, block the startup of cell cycle.Clinical test results (NCT00721409) shows, comes
The progresson free survival phase (Progression-free survival, PFS) of the patient of bent azoles single therapy is
7.5 months, its progresson free survival phase of patient of letrozole and the treatment of PD-0332991 drug combination was then
Extending to 26.1 months, this significant advantage obtains extensive concern, and at the beginning of 2013, FDA is in examination & verification
Think that this is probably a kind of breakthrough cancer therapy drug after the term results of this medicine.
WO2014183520 discloses the CDK4&6 inhibitor similar to PD-0332991 structure,
There is inhibitory activity and the high selectivity of significant CDK4&6, including following compound:
But WO2014183520 does not furthers investigate the crystal form of this compound.People in the art
Member is known, and the crystalline structure of medicinal active component often has influence on the chemical stability of this medicine,
The difference of crystallization condition and condition of storage is likely to result in the change of the crystalline structure of compound, has
Time also can along with produce other forms crystal formation.In general, unformed drug products does not has
Well-regulated crystalline structure, often has other defect, such as product stability poor, crystallize
Relatively thin, it is more difficult to filter, and easily lumps, poor fluidity etc..Therefore, each of above-claimed cpd is improved
Aspect character is necessary, it would be desirable to further investigation is found crystal form purity higher and has
The novel crystal forms of standby good chemical stability.
Summary of the invention
The invention provides 6-acetyl group-8-cyclopenta-5-methyl-2-((5-(piperidin-4-yl) pyridine-2-
Base) amino) pyrido [2,3-d] pyrimidine-7 (8H)-one (as shown in formula (I)),
The series of crystallization product that compound shown in formula (I) obtains under different crystallization conditions, right
Gained crystallized product has carried out X-diffraction and DSC detection, finds that compound shown in formula (I) exists
Under conventional crystallization condition, can obtain a kind of crystal formation having good stability, we are called I
Type crystallizes.In the application I type crystallization DSC collection of illustrative plates show have near 289.22 DEG C melted
Endothermic peak, X-ray powder diffraction spectrum is as it is shown in figure 1, use Cu-Ka radiation, with 2 θ angles
The X-ray powder diffraction spectrum that degree and interplanar distance (d value) represent, wherein 4.91 (17.99),
9.91 (8.92), 10.53 (8.39), 14.82 (5.98), 16.04 (5.52), 17.34 (5.11),
18.51 (4.79), 19.92 (4.45), 21.19 (4.19), 22.65 (3.92), 24.15 (3.68),
26.92 (3.31), and 28.98 (3.08) have characteristic peak.
Present invention also offers preparation 6-acetyl group-8-cyclopenta-5-methyl-2-((5-(piperidin-4-yl)
Pyridine-2-base) amino) pyrido [2,3-d] pyrimidine-7 (8H)-one I type crystallization method, described side
Method comprises the steps:
1) compound shown in any crystal formation or unformed formula (I) is added in appropriate solvent,
Add acid, molten clear after add alkali, crystallize, described solvent selected from carbon number less than or equal to 3
Alcohols, ketone, the mixed solvent of any one or they and water of nitrile；
2) filtering for crystallizing washing, is dried.
The most described acid is mineral acid, preferably hydrochloric acid；Described alkali is nothing
Machine alkali, preferably sodium bicarbonate or potassium bicarbonate.
Step 1 in preferred embodiments) described in solvent be methanol, ethanol, isopropanol,
Acetone, acetonitrile or methanol/water, ethanol/water, acetone/water, acetonitrile/water, isopropanol/water；Preferably
Ethanol.
The method of recrystallization is not particularly limited, and can carry out by common recrystallization operation method.
For example, it is possible to slowly cool down after organic solvent heating for dissolving with compound shown in raw material formula (I)
Crystallize, after having crystallized, through filtration drying, i.e. available required crystallization.Need to say especially
Bright, the crystalline solid of institute's leaching generally the most under reduced pressure, at about 30～100 DEG C, preferably 40～
It is vacuum dried under the heating condition of 60 DEG C, just can reach to remove the effect of recrystallization solvent.
Measured, to the formula (I) obtained by differential scanning calorimeter (DSC), X-diffracting spectrum
Shown compound crystal body has carried out crystal formation research, carries out the dissolvent residual of gained crystallization simultaneously
Detection.
Do not contain or only according to the crystallization of compound I type shown in formula (I) prepared by the method for the present invention
Containing the residual solvent of lower content, the relevant medical product residual meeting state-promulgated pharmacopoeia regulation is molten
The limitation requirement of agent, thus the crystallization of the present invention can preferably use as medicating active ingredients.
Show after deliberation, the crystallization of the I type of compound shown in formula (I) prepared by the present invention illumination,
Have good stability under conditions of high temperature, high humidity, and grinding, pressure and under the conditions of being heated etc.,
Stability of crystal form is good, it is possible to meet the medicinal requirements that production and transport stores, stable processing technique
Repeatable controlled, it is possible to be adapted to industrialized production.
Accompanying drawing explanation
The X-ray powder diffraction spectrum of the crystallization of compound I type shown in Fig. 1 formula (I).
The DSC collection of illustrative plates of the crystallization of compound I type shown in Fig. 2 formula (I).
Detailed description of the invention
The present invention being explained in greater detail below with reference to embodiment, embodiments of the invention are only used for
Technical scheme, and non-limiting the spirit and scope of the invention are described.
Test instrunment used by experiment
1, DSC spectrum
INSTRUMENT MODEL: MettlerToledo DSC 1 Staree System
Purge gas: nitrogen
Heating rate: 10.0 DEG C/min
Temperature range: 40-350 DEG C
2, x-ray diffraction pattern
INSTRUMENT MODEL: Bruker D8 Focus X-ray powder diffractometer
Ray: monochromatic Cu-K alpha ray (λ=1.5406)
Scan mode: θ/2 θ, sweep limits: 2-40 °
Voltage: 40KV, electric current: 40mA
Embodiment 1
Take compound shown in (1.0g, 2.24mmol) formula (I) (to carry by WO2014183520
Prepared by the method for confession) join in 250ml conical flask, add 40ml ethanol, stir under room temperature,
Then instill dilute hydrochloric acid (219mg, 6.01mmol) (being dissolved in 4ml water), be heated to 60 DEG C, molten
Clearly, instill in sodium bicarbonate solution (1.21g, 14.40mmol) (being dissolved in 40ml water), cooling
To stirred overnight at room temperature.Being dried to obtain solid 0.89g, yield is 89.0%.The X-of this crystallized sample
X ray diffraction spectrogram is shown in Fig. 1.This crystallization about 4.91 (17.99), 9.91 (8.92), 10.53 (8.39),
14.82 (5.98), 16.04 (5.52), 17.34 (5.11), 18.51 (4.79), 19.92 (4.45),
21.19 (4.19), 22.65 (3.92), 24.15 (3.68), 26.92 (3.31), and 28.98 (3.08)
There is characteristic peak at place.DSC spectrogram is shown in Fig. 2, has sharp-pointed melted endothermic peak 289.22 DEG C, by this crystal formation
It is defined as I crystal.
Embodiment 2
Take compound (preparing by embodiment 1) shown in (1.0g, 2.24mmol) formula (I) to add
Enter in 250ml conical flask, add 40ml methanol, stir under room temperature, then instill dilute hydrochloric acid
(219mg, 6.01mmol) (is dissolved in 4ml water), is heated to 60 DEG C, molten clearly, instill carbonic acid
In hydrogen sodium solution (1.21g, 14.40mmol) (being dissolved in 40ml water), it is cooled to be stirred at room temperature
Night.Being dried to obtain solid 0.98g, yield is 98.0%.Its X-diffraction and DSC collection of illustrative plates are after deliberation
Comparison, determines that product is I crystal.
Embodiment 3
Take compound (preparing by embodiment 1) shown in (1.0g, 2.24mmol) formula (I) to add
Enter in 250ml conical flask, add 40ml isopropanol, stir under room temperature, then instill dilute salt
Acid (219mg, 6.01mmol) (being dissolved in 4ml water), be heated to 60 DEG C, molten clearly, instill carbon
In acid hydrogen sodium solution (1.21g, 14.40mmol) (being dissolved in 40ml water), it is cooled to be stirred at room temperature
Overnight.Being dried to obtain solid 0.52g, yield is 52.0%.Its X-diffraction and DSC collection of illustrative plates are through grinding
Study carefully comparison, determine that product is I crystal.
Embodiment 4
Take compound (preparing by embodiment 1) shown in (1.0g, 2.24mmol) formula (I) to add
Enter in 250ml conical flask, add 40ml acetone, stir under room temperature, then instill dilute hydrochloric acid
(219mg, 6.01mmol) (is dissolved in 4ml water), is heated to 60 DEG C, molten clearly, instill carbonic acid
In hydrogen sodium solution (1.21g, 14.40mmol) (being dissolved in 40ml water), it is cooled to be stirred at room temperature
Night.Being dried to obtain solid 0.76g, yield is 76.0%.Its X-diffraction and DSC collection of illustrative plates are after deliberation
Comparison, determines that product is I crystal.
Embodiment 5
Take compound (preparing by embodiment 1) shown in (1.0g, 2.24mmol) formula (I) to add
Enter in 250ml conical flask, add 40ml acetonitrile, stir under room temperature, then instill dilute hydrochloric acid
(219mg, 6.01mmol) (is dissolved in 4ml water), is heated to 60 DEG C, molten clearly, instill carbon afterwards
In acid hydrogen sodium solution (1.21g, 14.40mmol) (being dissolved in 40ml water), it is cooled to be stirred at room temperature
Overnight.Drying solid 0.66g, yield is 66.0%.Its X-diffraction and DSC collection of illustrative plates are after deliberation
Comparison, determines that product is I crystal.
Embodiment 6
Divide placement by the most uncovered for the I type crystallized product sample of embodiment 1 gained, investigate at light
According to (4500Lux), heat (40 DEG C, 60 DEG C), under the conditions of high humidity (RH75%, RH90%)
The stability of sample.Investigate sample time be 5 days and 10 days, HPLC detect purity be shown in Table 1.
Shown in table 1, formula (I), the stability of compound I crystal sample compares
Study on the stability result shows that compound I type crystallized sample shown in formula (I) is in uncovered placement
Under conditions of, sample is under illumination and hot conditions, and sample is slightly degraded, under conditions of high humidity,
Stability is preferable.
Embodiment 7
Compound I type crystallization shown in the formula (I) that will prepare as embodiment 1 method is ground, adds
Heat and tabletting process, and result of study shows that stable crystal form, detailed experimental data see table 2 below.
The special stability study of compound I crystal shown in table 2. formula (I)
Claims (7)
1. the I type crystallization of compound as shown in formula (I), it is characterised in that: use Cu-Ka
Radiation, obtains the X-ray powder diffraction spectrum represented with 2 θ angles and interplanar distance, described knot
Crystalline substance has X-ray powder diffraction spectrum as shown in Figure 1, wherein about 4.91 (17.99),
9.91 (8.92), 10.53 (8.39), 14.82 (5.98), 16.04 (5.52), 17.34 (5.11),
18.51 (4.79), 19.92 (4.45), 21.19 (4.19), 22.65 (3.92), 24.15 (3.68),
26.92 (3.31), and 28.98 (3.08) have characteristic peak,
2. prepare the I type knot of compound as shown in formula (I) according to claim 1 for one kind
Brilliant method, described method comprises the steps:
1) compound shown in any crystal formation or unformed formula (I) is added in appropriate solvent,
Add acid, molten clear after add alkali, crystallize, described solvent selected from carbon number less than or equal to 3
Alcohols, ketone, the mixed solvent of any one or they and water of nitrile；
2) filtering for crystallizing washing, is dried.
Preparation method the most according to claim 2, wherein said acid is mineral acid, preferably
For hydrochloric acid.
Preparation method the most according to claim 2, wherein said alkali is inorganic base, preferably
For sodium bicarbonate or potassium bicarbonate.
Method the most according to claim 2, it is characterised in that in step 1) described in
Solvent be methanol, ethanol, isopropanol, acetone, acetonitrile or methanol/water, ethanol/water, acetone/
Water, acetonitrile/water, isopropanol/water；Preferred alcohol.
6. a pharmaceutical composition, it contains the chemical combination as shown in formula (I) described in claim 1
The I type crystallization of thing and pharmaceutically acceptable carrier.
The I type crystallization of compound as shown in formula (I) the most according to claim 1 or right
Require that the pharmaceutical composition described in 6 is at preparation treatment and cyclin dependent kinase
(CDK4&6) purposes in the medicine of relevant disease；The preferred breast carcinoma of described disease.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2015101939967 | 2015-04-22 | ||
| CN201510193996 | 2015-04-22 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106065016A true CN106065016A (en) | 2016-11-02 |
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| CN110790748A (en) * | 2018-08-02 | 2020-02-14 | 江苏豪森药业集团有限公司 | Crystal form of p-toluenesulfonate of cyclin dependent kinase inhibitor and preparation method and application thereof |
| WO2024193393A1 (en) * | 2023-03-17 | 2024-09-26 | 成都金瑞基业生物科技有限公司 | Crystal form of heteropyridopyrimidinone derivative and preparation method therefor |
| US12364697B2 (en) | 2018-01-08 | 2025-07-22 | Pharmacosmos Holding A/S | G1T38 superior dosage regimes |
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| WO2014183520A1 (en) * | 2013-05-17 | 2014-11-20 | 上海恒瑞医药有限公司 | Thiophene miazines derivate, preparation method therefor, and medical application thereof |
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| WO2014183520A1 (en) * | 2013-05-17 | 2014-11-20 | 上海恒瑞医药有限公司 | Thiophene miazines derivate, preparation method therefor, and medical application thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US12364697B2 (en) | 2018-01-08 | 2025-07-22 | Pharmacosmos Holding A/S | G1T38 superior dosage regimes |
| CN110790748A (en) * | 2018-08-02 | 2020-02-14 | 江苏豪森药业集团有限公司 | Crystal form of p-toluenesulfonate of cyclin dependent kinase inhibitor and preparation method and application thereof |
| CN110790748B (en) * | 2018-08-02 | 2022-04-19 | 江苏豪森药业集团有限公司 | Crystal form of p-toluenesulfonate of cyclin dependent kinase inhibitor and preparation method and application thereof |
| WO2024193393A1 (en) * | 2023-03-17 | 2024-09-26 | 成都金瑞基业生物科技有限公司 | Crystal form of heteropyridopyrimidinone derivative and preparation method therefor |
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