CN106065016B - A kind of crystal form and preparation method thereof of cyclin dependent kinase inhibitor - Google Patents
A kind of crystal form and preparation method thereof of cyclin dependent kinase inhibitor Download PDFInfo
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- CN106065016B CN106065016B CN201610248169.8A CN201610248169A CN106065016B CN 106065016 B CN106065016 B CN 106065016B CN 201610248169 A CN201610248169 A CN 201610248169A CN 106065016 B CN106065016 B CN 106065016B
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- 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
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Abstract
The present invention relates to a kind of crystal forms and preparation method thereof of cyclin dependent kinase inhibitor.Specifically, the present invention relates to the I type of a kind of cyclin dependent kinase (CDK4&6) inhibitor crystallizations and preparation method thereof.Specifically; the present invention relates to 6- acetyl group -8- cyclopenta -5- methyl -2- ((5- (piperidin-4-yl) pyridine -2- base) amino) pyridos [2; 3-d] pyrimidine -7 (8H) -one (formula (I) compound) I type crystallization and preparation method thereof, it is described crystallization have X-ray powder diffraction collection as shown in Figure 1.The I type crystallization of formula obtained by the present invention (I) compound has 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) pyrroles
Pyridine simultaneously [2,3-d] pyrimidine -7 (8H) -one and its I crystal.Formula (I) compound prepared according to the method for the present invention can be used for
The treatment of breast cancer.
Background technique
Breast cancer is one of the most common malignant tumors in women, has disease incidence high, has much invasion, but disease progression is slow
Slowly, Chinese population association has issued " Chinese mammary gland disease survey report " on 2 1st, 2010 in Beijing, report display, China city
The death rate of city area breast cancer increases 38.91%, and breast cancer, which has become, threatens maximum disease to WomanHealth, at present
At at least 156 kinds of the breast cancer medicines for grinding and listing, wherein 68% is target therapeutic agent, numerous studies find tumour and thin
Born of the same parents' period is unusual related, and the mass mutation of mitogenic signals albumen and antimitotic signal protein defect are led in tumour cell
Cause Proliferative Disorders；Simultaneously all there is genomic instability (GIN) and genome unstability (CIN) in most of tumour, this
Three kinds of basic cell cycle defects are all directly or indirectly caused by the out of control of CDKs.Cyclin dependent kinase (CDK,
Cyclin Dependent Kinase) inhibitor has become popular target.
There are many a generation two generations CDK inhibitor developed at present, two generation drugs of greatest concern include Pfizer company and
The CDK4&6 inhibitor PD-0332991 of Onyx company joint development inhibits the phosphoric acid of Rb by inhibiting the activity of CDK4&6
Change, makes the retention of E2F-Rb compound in endochylema, block the starting of cell cycle.Clinical test results (NCT00721409) are aobvious
To show, the progresson free survival phase (Progression-free survival, PFS) of the patient of Letrozole single therapy is 7.5 months,
And the patient of Letrozole and the treatment of PD-0332991 drug combination then extends to 26.1 months its progresson free survival phase, this is significant excellent
Gesture obtains extensive concern, and FDA thinks that this may be a kind of breakthrough after the term results for having audited this drug at the beginning of 2013
The anticancer drug of property.
WO2014183520 discloses CDK4&6 inhibitor similar with PD-0332991 structure, has significant CDK4&6
Inhibitory activity and high selectivity, including following compound:
But WO2014183520 does not further investigate the crystal form of the compound.It is well known to those skilled in the art, it is medicinal
The crystalline structure of active constituent often influences the chemical stability of the drug, and the difference of crystallization condition and condition of storage is possible to
Lead to the variation of the crystalline structure of compound, it sometimes can also be along with the crystal form for generating other forms.In general, unformed
Drug products do not have well-regulated crystalline structure, and often poor with other defects, such as product stability, crystallization is thinner, filtering
It is more difficult, easily agglomerate, poor fluidity etc..Therefore, it is necessary for improving each side's surface properties of above compound, it would be desirable to deep
Entering research, to find crystal form purity higher and have the novel crystal forms of good chemical stability.
Summary of the invention
The present 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, to gained crystallized product into
Gone X- diffraction and DSC detection, find compound shown in formula (I) under conventional crystallization condition, a kind of available stability
Good crystal form, we are called the crystallization of I type.In the application I type crystallization DSC map be shown in 289.22 DEG C nearby have it is molten
Melt endothermic peak, X-ray powder diffraction collection using Cu-Ka as shown in Figure 1, radiate, with 2 θ angles and interplanar distance (d value) table
The X-ray powder diffraction collection shown, wherein in 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), there are characteristic peak in 26.92 (3.31) and 28.98 (3.08).
The present invention also provides 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, the method includes the following steps:
1) compound shown in any crystal form or unformed formula (I) is added in suitable solvent, acid is added, adds after dissolved clarification
Enter alkali, crystallization, the solvent is selected from any one or they and the water of alcohols of the carbon atom number less than or equal to 3, ketone, nitrile
Mixed solvent；
2) it filtering for crystallizing and washs, it is dry.
The acid is inorganic acid, preferably hydrochloric acid in preferred embodiments；The alkali is inorganic base, preferably carbonic acid
Hydrogen sodium or saleratus.
Solvent described in step 1) is methanol, ethyl alcohol, isopropanol, acetone, acetonitrile or first in preferred embodiments
Alcohol/water, ethanol/water, acetone/water, acetonitrile/water, isopropanol/water；Preferred alcohol.
The method of recrystallization is not particularly limited, and can be carried out with common recrystallization operation method.For example, original can be used
The slowly cooling crystallization after organic solvent heating for dissolving of compound shown in material formula (I), after the completion of crystallization, through filtration drying
Obtain required crystallization.Specifically, the crystalline solid of institute's leaching is usually under reduced pressure, excellent at 30~100 DEG C or so
It selects and is dried in vacuo under 40~60 DEG C of heating condition, can achieve the effect that remove recrystallization solvent.
It is measured by differential scanning calorimeter (DSC), X- diffracting spectrum, to compound crystalline solid shown in obtained formula (I)
Crystal form research has been carried out, while the dissolvent residual of gained crystallization has been detected.
Compound I type crystallization shown in the formula (I) of the method according to the invention preparation does not contain or only containing lower content
Residual solvent meets the limitation requirement in relation to medical product residual solvent as defined in National Pharmacopeia, thus crystallization of the invention can
Preferably to be used as medicating active ingredients.
Research has shown that the I type of compound shown in formula (I) prepared by the present invention is crystallized in illumination, the condition of high temperature, high humidity
Stability inferior is good, and grinding, pressure and it is heated etc. under the conditions ofs, stability of crystal form is good, can satisfy production and transport storage
Medicinal requirements, stable processing technique is repeatable controllable, can adapt in industrialized production.
Detailed description of the invention
The X-ray powder diffraction collection of the crystallization of compound I type shown in Fig. 1 formula (I).
The DSC map of the crystallization of compound I type shown in Fig. 2 formula (I).
Specific embodiment
The present invention is explained in greater detail below with reference to embodiment, the embodiment of the present invention is merely to illustrate skill of the invention
Art scheme, and non-limiting the spirit and scope of the invention.
Experiment test equipment used
1, DSC is composed
Instrument model: 1 Staree System of MettlerToledo DSC
Purge gass: 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 diffraction instrument
Ray: monochromatic Cu-K alpha ray (λ=1.5406)
Scanning mode: the θ of θ/2, scanning range: 2-40 °
Voltage: 40KV, electric current: 40mA
Embodiment 1
Compound shown in (1.0g, 2.24mmol) formula (I) (preparing by the method that WO2014183520 is provided) is taken to be added to
In 250ml conical flask, 40ml ethyl alcohol is added, stirs at room temperature, then instills dilute hydrochloric acid (219mg, 6.01mmol) and (be dissolved in 4ml
Water), 60 DEG C are heated to, dissolved clarification instills in sodium bicarbonate solution (1.21g, 14.40mmol) (being dissolved in 40ml water), is cooled to room
Temperature is stirred overnight.Dry solid 0.89g, yield 89.0%.The X-ray diffraction spectrogram of the crystallized sample is shown in Fig. 1.The knot
Crystalline substance 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
There is characteristic peak at 28.98 (3.08).DSC spectrogram is shown in Fig. 2, there is sharp 289.22 DEG C of endothermic peak of melting, this crystal form is defined as I crystalline substance
Type.
Embodiment 2
It takes compound shown in (1.0g, 2.24mmol) formula (I) (preparing by embodiment 1) to be added in 250ml conical flask, adds
Enter 40ml methanol, stir at room temperature, then instills dilute hydrochloric acid (219mg, 6.01mmol) (being dissolved in 4ml water), be heated to 60 DEG C, it is molten
Clearly, it instills in sodium bicarbonate solution (1.21g, 14.40mmol) (being dissolved in 40ml water), is cooled to and is stirred overnight at room temperature.Dry
Solid 0.98g, yield 98.0%.Its X- diffraction and DSC map are compared through research, determine that product is I crystal.
Embodiment 3
It takes compound shown in (1.0g, 2.24mmol) formula (I) (preparing by embodiment 1) to be added in 250ml conical flask, adds
Enter 40ml isopropanol, stir at room temperature, then instills dilute hydrochloric acid (219mg, 6.01mmol) (being dissolved in 4ml water), be heated to 60 DEG C,
Dissolved clarification instills in sodium bicarbonate solution (1.21g, 14.40mmol) (being dissolved in 40ml water), is cooled to and is stirred overnight at room temperature.It is dry
Obtain solid 0.52g, yield 52.0%.Its X- diffraction and DSC map are compared through research, determine that product is I crystal.
Embodiment 4
It takes compound shown in (1.0g, 2.24mmol) formula (I) (preparing by embodiment 1) to be added in 250ml conical flask, adds
Enter 40ml acetone, stir at room temperature, then instills dilute hydrochloric acid (219mg, 6.01mmol) (being dissolved in 4ml water), be heated to 60 DEG C, it is molten
Clearly, it instills in sodium bicarbonate solution (1.21g, 14.40mmol) (being dissolved in 40ml water), is cooled to and is stirred overnight at room temperature.Dry
Solid 0.76g, yield 76.0%.Its X- diffraction and DSC map are compared through research, determine that product is I crystal.
Embodiment 5
It takes compound shown in (1.0g, 2.24mmol) formula (I) (preparing by embodiment 1) to be added in 250ml conical flask, adds
Enter 40ml acetonitrile, stir at room temperature, then instills dilute hydrochloric acid (219mg, 6.01mmol) (being dissolved in 4ml water), be heated to 60 DEG C, it is molten
Clearly, it instills in sodium bicarbonate solution (1.21g, 14.40mmol) (being dissolved in 40ml water) afterwards, is cooled to and is stirred overnight at room temperature.It is dry
Solid 0.66g, yield 66.0%.Its X- diffraction and DSC map are compared through research, determine that product is I crystal.
Embodiment 6
By the resulting I type crystallized product sample of embodiment 1, opening divides placement respectively, investigates at illumination (4500Lux), adds
Hot (40 DEG C, 60 DEG C), the stability of sample under the conditions of high humidity (RH75%, RH90%).Investigating sample time is 5 days and 10 days,
HPLC detection purity is shown in Table 1.
The stability of compound I crystal sample shown in table 1, formula (I) compares
The result shows that compound I type crystallized sample shown in formula (I) is under conditions of opening is placed, sample exists study on the stability
Under illumination and hot conditions, sample is slightly degraded, and under conditions of high humidity, stability is then preferable.
Embodiment 7
It will be crystallized by compound I type shown in formula (I) made from 1 method of embodiment and be ground, be heated and compressing tablet process, ground
Study carefully the result shows that stable crystal form, detailed experimental data is referring to the following table 2.
The special stability study of compound I crystal shown in 2. formula of table (I)
Claims (11)
1. the I type of the compound as shown in formula (I) crystallizes, it is characterised in that: radiated, obtained with 2 θ angles and crystal face using Cu-Ka
The X-ray powder diffraction collection that spacing indicates, the crystallization have X-ray powder diffraction collection 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
There are characteristic peak in 28.98 (3.08),
2. a kind of method for the I type crystallization for preparing the compound according to claim 1 as shown in formula (I), the method packet
Include following step:
1) compound shown in any crystal form or unformed formula (I) is added in suitable solvent, acid is added, is added after dissolved clarification
Alkali, crystallization, the solvent are selected from the mixed of alcohols of the carbon atom number less than or equal to 3, ketone, any one or they of nitrile and water
Bonding solvent；
2) it filtering for crystallizing and washs, it is dry.
3. preparation method according to claim 2, wherein the acid is inorganic acid.
4. preparation method according to claim 3, wherein the acid is hydrochloric acid.
5. preparation method according to claim 2, wherein the alkali is inorganic base.
6. preparation method according to claim 5, wherein the alkali is sodium hydroxide or potassium hydroxide.
7. preparation method according to claim 2, it is characterised in that solvent described in step 1) be methanol, ethyl alcohol,
Isopropanol, acetone, acetonitrile or methanol/water, ethanol/water, acetone/water, acetonitrile/water, isopropanol/water.
8. preparation method according to claim 7, it is characterised in that solvent described in the step 1) is ethyl alcohol.
9. a kind of pharmaceutical composition, the crystallization of I type and pharmacy containing the compound described in claim 1 as shown in formula (I)
Upper acceptable carrier.
10. the I type of the compound according to claim 1 as shown in formula (I) crystallizes or pharmaceutical composition as claimed in claim 9
Purposes of the object in the drug of preparation treatment and cyclin dependent kinase (CDK4&6) related disease.
11. purposes according to claim 10, wherein the disease is breast cancer.
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| CN2015101939967 | 2015-04-22 | ||
| CN201510193996 | 2015-04-22 |
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| 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 |
| CN116284044A (en) * | 2023-03-17 | 2023-06-23 | 上海勋和医药科技有限公司 | Crystal form and preparation method of hybrid pyridopyrimidinone derivative |
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| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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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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