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
- Publication number
- CN106065016A CN106065016A CN201610248169.8A CN201610248169A CN106065016A CN 106065016 A CN106065016 A CN 106065016A CN 201610248169 A CN201610248169 A CN 201610248169A CN 106065016 A CN106065016 A CN 106065016A
- Authority
- CN
- China
- Prior art keywords
- formula
- water
- compound
- preparation
- crystallization
- 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.)
- Granted
Links
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 |
|---|---|---|---|
| CN201510193996 | 2015-04-22 | ||
| CN2015101939967 | 2015-04-22 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106065016A true CN106065016A (en) | 2016-11-02 |
| CN106065016B CN106065016B (en) | 2019-03-12 |
Family
ID=57419190
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610248169.8A Active CN106065016B (en) | 2015-04-22 | 2016-04-20 | A kind of crystal form and preparation method thereof of cyclin dependent kinase inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106065016B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2016
- 2016-04-20 CN CN201610248169.8A patent/CN106065016B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106065016B (en) | 2019-03-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103974949B (en) | A kind of I type crystallization of 2-maleate of tyrosine kinase inhibitor and preparation method | |
| CN106661025B (en) | A kind of isethionate of cyclin dependent kinase inhibitor, its crystal form and preparation method | |
| CN105980389B (en) | A kind of crystal form of disulfate of jak kinase inhibitor and preparation method thereof | |
| KR20120113285A (en) | Polymorphs of dasatinib, preparation methods and pharmaceutical compositions thereof | |
| CN106795159B (en) | A kind of crystal form and preparation method thereof of cyclin dependent kinase inhibitor | |
| WO2020244612A1 (en) | Polymorph of cdk9 inhibitor and preparation method for polymorph and use thereof | |
| CN108779122A (en) | A kind of crystal form of disulfate and preparation method thereof of jak kinase inhibitor | |
| US9593117B2 (en) | Crystalline form of N,N-dicyclopropyl-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide for the treatment of myeloproliferative disorders | |
| CN106065016A (en) | A kind of crystal form of cyclin dependent kinase inhibitor and preparation method thereof | |
| CN103059013B (en) | Crystal formation of Dasatinib monohydrate and preparation method thereof | |
| US9598413B2 (en) | Crystalline form of N,N-dicyclopropyl-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-D]pyrrolo[2,3-B]pyridine-7-carboxamide for the treatment of myeloproliferative disorders | |
| US9593116B2 (en) | Crystalline forms of N,N-dicyclopropyl-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide for the treatment of myeloproliferative disorders | |
| WO2020083188A1 (en) | Crystal form of maleate of tyrosine kinase inhibitor and preparation method therefor | |
| CN105992769A (en) | L-proline compound of sodium-glucose cotransporter 2 inhibitor, and monohydrate and crystal of l-proline compound | |
| JP2022540466A (en) | amorphous umbularisib monotosylate | |
| EP3941472A1 (en) | <smallcaps/>? ? ?n? ? ? ? ?crystalline and amorphous forms of-(5-((4-ethylpiperazin-1-yl)methyl)pyridine-2-yl)-5-fluoro-4-(3-isopropyl-2-methyl-2 <ns1:i>h</ns1:i>?-indazol-5-yl)pyrimidin-2-amine and its salts, and preparation methods and therapeutic uses thereof | |
| CN109963855A (en) | A kind of crystal form and preparation method of BTK kinase inhibitor | |
| CN105085421B (en) | Bit piperazine fumarate difficult to understand, hydrate, crystal formation and preparation method thereof | |
| CN106117199A (en) | The dihydroxy ethyl sulfonate of a kind of cell cycle protein dependent kinase inhibitor, its crystal form and preparation method thereof | |
| TW201125861A (en) | CDC7 inhibitor salts | |
| CN109476667A (en) | The solid form of TTK inhibitor | |
| CN106432243B (en) | Crystal form of hedgehog signal pathway inhibitor and preparation method thereof | |
| CN106432244A (en) | Crystallization form of hedgehog signal pathway inhibitor, and preparation method thereof | |
| CN109206407A (en) | A kind of crystal form of 2-maleate of tyrosine kinase inhibitor and preparation method thereof | |
| WO2016101912A1 (en) | Crystal form of salt of epidermal growth factor receptor kinase inhibitor and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |