CN105111215B - A kind of crystal form and preparation method thereof of cyclin-dependent kinase inhibitor - Google Patents

Abstract

The present invention relates to 7- cyclopenta -2- (5- piperazine -1- base-pyridine -2- base amino) -7H- pyrrolo-es [2,3-D] pyrimidine -6- carboxylic acid diformamide hemisuccinic acid salt novel crystal forms and preparation method thereof, the novel crystal forms and preparation method thereof of monosuccinic acid salt.The hemisuccinic acid salt novel crystal forms of formula (I) compound of the invention, monosuccinic acid salt novel crystal forms, it is with good stability, lower to draw moist, technique and develop and the advantageous properties such as tractability, and preparation method is simple, it is low in cost, there is important value to the optimization and exploitation of the following drug.

Description

A kind of crystal form and preparation method thereof of cyclin-dependent kinase inhibitor

Technical field

The present invention relates to chemical medicines, more particularly to 7- cyclopenta -2- (5- piperazine -1- base-pyridine -2- base ammonia Base) -7H- pyrrolo- [2,3-D] pyrimidine -6- carboxylic acid diformamide hemisuccinic acid salt crystal form.

Background technique

(cyclin-dependent kinase4/6, CDK4/6) is a kind of silk/Soviet Union's ammonia for Cyclin dependent kinase 4/6 Acid kinase is combined with cyclin D (cyclinD), is adjusted cell from G1 phase to the S phase and is converted in many tumours, all exists The change of this access of " cyclinD-CDK4/6-INK4-Rb access " exception, accelerates G1 phase process, so that tumour cell increases It grows quickening and obtains survival advantage.Therefore, a kind of therapeutic strategy is become to its intervention, therefore CDK4/6 becomes antitumor target One of point.

LEE011 is a kind of little molecules in inhibiting object of Cyclin dependent kinase 4/6, is researched and developed and is used by Novartis In treatment drug resistance breast cancer and melanoma drug, LEE011 clinical use is its succinate, in preclinical study Performance is good, obtains positive research achievement, is currently in during the clinical III phase studies.The chemical name of LEE011 is 7- ring Amyl -2- (5- piperazine -1- base-pyridine -2- base amino) -7H- pyrrolo- [2,3-D] pyrimidine -6- carboxylic acid diformamide, structure As shown in formula (I):

Currently, patent CN103201275 protect formula (I) compound monosuccinic acid salt a hydrate crystal forms and one Anhydrous crystal forms.Other drugmakers there is no to disclose the polymorphic of formula (I) compound or the polymorphic of its salt.

The present inventor has found that existing monosuccinic acid salt crystal form humidity stability is low in the course of the research, easily turns at high humidity Other crystal forms are turned to, the exploitation and storage of drug are unfavorable for.

Based on this, it is necessary to further develop good stability, low in hygroscopicity, the crystalline substance for being suitble to storage and industrialized production Type, to meet the subsequent development needs of drug.

Summary of the invention

The present invention provides a kind of novel crystal forms of hemisuccinic acid salt of formula (I) compound and its preparation methods and a kind of single amber The novel crystal forms and preparation method thereof of amber hydrochlorate.Novel crystal forms provided by the invention are suitable for drug research and industrialized production.

It is an object of the present invention to provide the novel crystal forms and preparation method thereof of formula (I) compound hemisuccinic acid salt.

Specifically, the present invention provides a kind of novel crystal forms of formula (I) compound hemisuccinic acid salt, is named as crystal form in the present invention A。

Specifically, crystal form A provided by the invention, which is characterized in that its X-ray powder diffraction figure is in 2theta value There is characteristic peak at 23.9 ° ± 0.2 °, 20.0 ° ± 0.2 °, 22.1 ° ± 0.2 °.

Further, crystal form A provided by the invention, it is further characterized in that, X-ray powder diffraction figure is in 2theta value To have characteristic peak at 22.0 ° ± 0.2 °, 21.3 ° ± 0.2 °, 13.0 ° ± 0.2 °.

Further, crystal form A provided by the invention, it is further characterized in that, X-ray powder diffraction figure is in 2theta value To have characteristic peak at 4.7 ° ± 0.2 °, 14.2 ° ± 0.2 °, 26.2 ° ± 0.2 °.

Further, crystal form A provided by the invention, which is characterized in that its X-ray powder diffraction figure is basic such as Fig. 1 institute Show.

It is a further object to provide the preparation method of formula (I) compound hemisuccinic acid salt crystal form A, feature exists In preparation method includes that formula (I) compound reacts in alcohols, alkyl nitrile, ether solvent with succinic acid, stirring and crystallizing It obtains.

Further, the alcohols solvent preferred alcohol, the preferred acetonitrile of alkyl nitrile solvents, the ether solvent Tetrahydrofuran.

Further, formula (I) compound and succinic acid react molar ratio between 1:0.4 to 1:1.

Compared with prior art, the hemisuccinic acid salt crystal form A that this patent provides has higher physical stability, specific table It is now that can be stabilized under the conditions of different humidity.On the other hand, monosuccinic acid salt in the prior art is in different solvents item Hemisuccinic acid salt disclosed in this patent is easily converted under part, the poor reproducibility of process exploitation is unfavorable for development and application.Another party Face, for hemisuccinic acid salt compared with monosuccinic acid salt, pharmaceutical ingredient content is higher.Compared with monosuccinic acid salt, hemisuccinic acid salt Acid lower, more conducively drug is absorbed and utilized, and plays drug effect.

It is a further object to provide a kind of novel crystal forms of formula (I) compound monosuccinic acid salt, ordered in the present invention Entitled crystal form I.

Crystal form I provided by the invention, which is characterized in that its X-ray powder diffraction figure 2theta value be 11.9 ° ± There is characteristic peak at 0.2 °, 19.4 ° ± 0.2 °, 20.5 ° ± 0.2 °.

Further, crystal form I provided by the invention, it is further characterized in that, X-ray powder diffraction figure is in 2theta value To have characteristic peak at 22.7 ° ± 0.2 °, 24.4 ° ± 0.2 °, 26.3 ° ± 0.2 °.

Further, crystal form I provided by the invention, it is further characterized in that, X-ray powder diffraction figure is in 2theta value To have characteristic peak at 7.8 ° ± 0.2 °, 15.7 ° ± 0.2 °, 16.7 ° ± 0.2 °.

Further, crystal form I provided by the invention, which is characterized in that its X-ray powder diffraction figure is basic such as Fig. 4 institute Show.

Crystal form I provided by the invention, which is characterized in that nearby start endothermic peak occur being heated to 197 DEG C, differential is swept It is substantially as shown in Figure 5 to retouch thermometric analysis figure.

Crystal form I provided by the invention, which is characterized in that when being heated to 177.5 DEG C, with about 2.0% weight loss Gradient, thermogravimetric analysis figure are substantially as shown in Figure 6.

It is a further object to provide the preparation method of formula (I) compound monosuccinic acid salt crystal form I, feature exists In preparation method includes that formula (I) compound and succinic acid are obtained in the in the mixed solvent stirring and crystallizing of alcohol, alkyl nitrile and alkane It arrives.

Further, the mixing of the mixed solvent or methanol and acetonitrile of the mixed solvent preferred alcohol and normal heptane Solvent.

Further, formula (I) compound and succinic acid react molar ratio between 1:0.8 to 1:2.

Crystal form I provided by the invention have it is lower draw it is moist, during the preparation process be not necessarily to special drying condition, simplify The preparation of drug and aftertreatment technology, it is easy to industrialized production.It is not harsh due to requiring condition of storage, greatly reduce object Material storage and quality control cost.Compared with patent crystal form, the stability of crystal form I is preferable, is not easy to turn crystalline substance during storage, With very strong economic value.

Or mixtures thereof formula (I) compound hemisuccinic acid salt crystal form A provided by the invention, monosuccinic acid salt crystal form I are available In the preparation for the treatment of cancer drug, especially for treating the preparation of drug resistance breast cancer and melanoma drug.

Pharmaceutical composition is to be with or mixtures thereof formula (I) compound hemisuccinic acid salt crystal form A, monosuccinic acid salt crystal form I Active constituent, addition drug are often prepared with auxiliary material.

Detailed description of the invention

The XRPD that Fig. 1 is hemisuccinic acid salt crystal form A schemes

Fig. 2 is hemisuccinic acid salt crystal form A's¹H NMR figure

The DVS that Fig. 3 is hemisuccinic acid salt crystal form A schemes

Fig. 4 is the hygroscopicity test XRPD comparison diagram of hemisuccinic acid salt crystal form A: the following figure is the XRPD figure before experiment, upper figure (crystal form is constant) is schemed for the XRPD after experiment

The XRPD that Fig. 5 is monosuccinic acid salt crystal form I schemes

The DSC that Fig. 6 is monosuccinic acid salt crystal form I schemes

The TGA that Fig. 7 is monosuccinic acid salt crystal form I schemes

The DVS that Fig. 8 is monosuccinic acid salt crystal form I schemes

Fig. 9 is the hygroscopicity test XRPD comparison diagram of monosuccinic acid salt crystal form I: the following figure is the XRPD figure before experiment, upper figure (crystal form is constant) is schemed for the XRPD after experiment

Figure 10 is that the DVS of patent CN103201275 monosuccinic acid salt anhydrous crystal forms schemes

Figure 11 is the hygroscopicity test XRPD comparison diagram of patent CN103201275 monosuccinic acid salt anhydrous crystal forms: the following figure is XRPD figure before experiment, upper figure are the XRPD figure (crystal form change) after experiment

Specific embodiment

Below will by specific embodiment, the present invention is further explained, but the protection scope being not intended to restrict the invention. Those skilled in the art can be made improvements to preparation method and using instrument within the scope of the claims, these improvement also should be regarded as Protection scope of the present invention.Therefore, the scope of protection of the patent of the invention shall be subject to the appended claims.

Used abbreviation is explained as follows in the present invention:

XRPD:X ray powder diffraction

DSC: differential scanning calorimetric analysis

TGA: thermogravimetric analysis

DVS: dynamic water absorption

¹H NMR: nuclear magnetic resonance spectroscopy

X-ray powder diffraction figure of the present invention is adopted on Panalytical Empyrean x-ray powder diffraction instrument Collection.The method parameter of X-ray powder diffraction of the present invention is as follows:

X ray reflection parameter: Cu, K α

1.540598；1.544426

1 intensity of K α 2/K α: 0.50

Voltage: 45 volt (kV)

Electric current: 40 milliamperes (mA)

Divergent slit: automatic

Scan pattern: continuous

Scanning range: from 3.0 to 40.0 degree

Sampling step length: 0.013 degree

Differential scanning calorimetric analysis (DSC) figure of the present invention acquires on TA Q2000.Differential of the present invention The method parameter for scanning thermometric analysis (DSC) is as follows:

Sweep speed: 10 DEG C/min

Protective gas: nitrogen

Thermogravimetric analysis (TGA) figure of the present invention acquires on TA Q5000.Thermogravimetric analysis (TGA) of the present invention Method parameter it is as follows:

Sweep speed: 10 DEG C/min

Protective gas: nitrogen

Dynamic water absorption (DVS) figure of the present invention is by SMS company (Surface Measurement Systems Ltd. it) is acquired on the Intrinsic dynamic water adsorption instrument produced.The method parameter of the dynamic water adsorption instrument is as follows:

Temperature: 25 DEG C

Carrier gas, flow velocity: N₂, 200 ml/mins

Unit time mass change: 0.002%/minute

RH range: 0%RH-95%RH

Embodiment 1

The preparation method of hemisuccinic acid salt crystal form A:

10.5mg formula (I) compound as its free base is taken to be dissolved in ethyl alcohol, the succinic acid of 3.0mg is added, and to stir 12 at room temperature small When, crystallization obtains.The crystal form A that the present embodiment obtains by XRPD, DSC, TGA and¹H NMR detection.Its X-ray powder diffraction number According to as shown in table 1.DSC data is shown, is heated to occurring endothermic peak at 180 DEG C, and TGA data, which are shown from room temperature, is heated to 118 DEG C There is 12.5% weightlessness.Its XRPD figure such as Fig. 1,¹H NMR figure such as Fig. 2.

Formula (I) compound hemisuccinic acid salt that the above method is prepared,¹H NMR appraising datum is as follows:

¹H NMR (400MHz, DMSO) δ 9.29 (s, 1H), 8.76 (s, 1H), 8.16 (d, J=9.0Hz, 1H), 8.00 (d, J=2.9Hz, 1H), 7.44 (dd, J=9.2,3.0Hz, 1H), 6.60 (s, 1H), 3.15-2.93 (m, 14H), 2.32 (s, 2H), 1.98(s,4H),1.65(s,2H).

Table 1

2theta	The interval d	Relative intensity %
			4.69	18.84	71.02
8.87	9.97	23.85
			9.45	9.36	16.73
10.64	8.32	41.57
			12.96	6.83	23.59
14.24	6.22	63.46
			15.73	5.63	7.33
16.17	5.48	18.29
			16.47	5.38	6.10
17.83	4.97	34.08
			18.26	4.86	20.26
18.47	4.80	37.64
			19.04	4.66	51.36
19.89	4.46	34.73
			20.04	4.43	40.63
20.70	4.29	11.44
			21.29	4.17	100.00
21.57	4.12	17.28
			22.04	4.03	40.12
22.20	4.00	40.13
			22.61	3.93	7.68
23.88	3.73	78.70
			24.32	3.66	25.92
25.33	3.52	7.29
			26.20	3.40	6.47
26.72	3.34	24.03
			27.83	3.21	7.19
28.78	3.10	11.72
			31.42	2.85	5.46
32.50	2.76	2.50
			33.72	2.66	5.12
38.65	2.33	2.58

Embodiment 2

The preparation method of hemisuccinic acid salt crystal form A:

10.2mg formula (I) compound as its free base is taken to be dissolved in tetrahydrofuran, the succinic acid that 2.8mg is added stirs 12 at room temperature Hour, crystallization obtains.The X-ray powder diffraction data for the crystal form A that the present embodiment obtains are as shown in table 2.

Table 2

2theta	The interval d	Relative intensity %
			4.70	18.81	100.00
6.14	14.40	13.17
			8.87	9.96	12.08
10.65	8.31	24.56
			12.32	7.18	7.43
12.97	6.82	23.94
			14.28	6.20	67.09
16.18	5.48	21.53
			17.87	4.96	34.36
18.49	4.80	56.14
			19.10	4.65	60.98
20.08	4.42	49.94
			20.72	4.29	19.08
21.32	4.17	60.86
			21.56	4.12	28.62
22.04	4.03	54.18
			22.21	4.00	43.36
22.64	3.93	11.04
			23.49	3.79	16.24
23.89	3.72	87.76
			24.36	3.65	31.70
25.31	3.52	16.68
			26.24	3.40	13.04
26.75	3.33	33.25
			27.87	3.20	16.12
28.82	3.10	14.01
			30.60	2.92	5.00
31.43	2.85	12.77
			32.60	2.75	5.05

33.72	2.66	7.39
			35.71	2.51	5.65
38.62	2.33	4.11

Embodiment 3

Stability study under hemisuccinic acid salt crystal form A high humidity:

It takes crystal form A about 10mg of the invention to carry out dynamic water absorption using dynamic water absorption (DVS) instrument to test, and XRPD is detected respectively in test front and back.The results show that crystal form A of the invention is 3.543% in the weight gain of 80% relative humidity, draw wet Property it is lower, DVS figure is as shown in Figure 3.Crystal form is constant before and after dynamic water absorption test, and XRPD comparison diagram is as shown in Figure 4.

Define that (Chinese Pharmacopoeia version annex XIX J drug in 2010 draws with draw moist weight gain about the description of moist feature is drawn Moist test direction principle, experiment condition: 25 DEG C ± 1 DEG C, 80% relative humidity):

It deliquesces: absorbing enough moisture and form liquid

It is great draw it is moist: draw wet weight gain not less than 15%

Have draw it is moist: draw wet weight gain less than 15% but not less than 2%

Slightly draw moist: drawing wet weight gain less than 2% but not less than 0.2%

Nothing is moist almost without drawing: drawing wet weight gain less than 0.2%

Embodiment 4

The transformation relationship research of monosuccinic acid salt anhydrous crystal forms in crystal form A and patent CN103201275 of the invention:

By monosuccinic acid salt anhydrous crystal forms in about 10mg patent CN103201275 as starting crystal form, it is added different molten In agent or mixed solvent (volume ratio), after stirring 48 hours under 5~50 degrees Celsius, final transformation of crystal is the crystalline substance in the present invention Type A.The present embodiment solvent for use is as shown in table 3.

Table 3

Embodiment 5

The preparation method of monosuccinic acid salt crystal form I:

30.7mg monosuccinic acid salt anhydrous crystal forms (being prepared by patent CN103201275) are taken to be dissolved in 2.2mL acetonitrile: Methanol volume ratio is the in the mixed solvent of 10:1, stirs 48 hours crystallizations under the conditions of 50 DEG C and obtains.

The X-ray powder diffraction data for the crystal form I that the present embodiment obtains are as shown in table 4.Its XRPD figure such as Fig. 5, DSC figure Such as Fig. 6, TGA figure such as Fig. 7.

Table 4

2theta	The interval d	Relative intensity %
			6.83	12.95	7.85
7.82	11.30	16.06
			11.24	7.88	3.49
11.88	7.45	53.46
			12.46	7.11	5.71
13.06	6.78	19.20
			13.31	6.65	31.18
14.01	6.32	16.85
			15.71	5.64	20.66
16.29	5.44	6.07
			16.70	5.31	21.23
17.81	4.98	71.41
			18.63	4.76	18.63

19.35	4.59	31.47
			19.69	4.51	8.47
20.10	4.42	32.20
			20.47	4.34	43.73
20.64	4.30	100.00
			21.23	4.19	16.26
21.72	4.09	6.12
			22.74	3.91	61.23
23.12	3.85	15.91
			23.34	3.81	6.29
23.89	3.73	5.74
			24.43	3.64	66.75
25.11	3.55	4.94
			25.80	3.45	7.99
26.27	3.39	23.61
			27.61	3.23	8.03
27.99	3.19	4.23
			28.44	3.14	82.46
28.52	3.14	46.44
			29.18	3.06	14.13
29.74	3.00	3.00
			30.04	2.97	3.93
30.82	2.90	3.98
			31.16	2.87	3.74
31.59	2.83	4.01
			32.27	2.77	3.61
33.08	2.71	7.40
			34.21	2.62	2.30
36.23	2.48	3.61
			37.35	2.41	1.65
38.69	2.33	1.28

Embodiment 6

The preparation method of monosuccinic acid salt crystal form I:

3.1mg monosuccinic acid salt anhydrous crystal forms (being prepared by patent CN103201275) are taken to be dissolved in 0.5mL ethyl alcohol: Normal heptane volume ratio is the in the mixed solvent of 4:1, stirs 48 hours crystallizations at room temperature and obtains.

The X-ray powder diffraction data for the crystal form I that the present embodiment obtains are as shown in table 5.

Table 5

2theta	The interval d	Relative intensity %
			6.83	12.95	11.44
7.84	11.28	26.24
			11.90	7.44	88.02
13.09	6.77	21.52
			13.33	6.64	35.24
14.02	6.31	15.85
			15.74	5.63	23.50
16.71	5.31	18.54
			17.83	4.98	76.15
18.64	4.76	22.51
			19.37	4.58	31.64
20.11	4.41	28.17
			20.65	4.30	100.00
21.26	4.18	14.82
			22.22	4.00	5.89
22.76	3.91	63.69
			23.15	3.84	17.57
24.44	3.64	71.31
			25.12	3.54	7.95
25.81	3.45	8.77
			26.29	3.39	19.56
27.59	3.23	5.79
			28.16	3.17	1.30
29.20	3.06	17.50
			30.11	2.97	4.35
30.85	2.90	5.16
			32.30	2.77	4.95
33.11	2.71	7.22
			34.25	2.62	2.79
36.26	2.48	3.54

Embodiment 7

The stability of crystal form I of the present invention and patent CN103201275 monosuccinic acid salt anhydrous crystal forms under high humidity conditions Research:

Taking the monosuccinic acid salt anhydrous crystal forms of crystal form I and patent CN103201275 of the invention, respectively about 10mg is respectively adopted Dynamic water absorption (DVS) instrument test is drawn moist.And draws moist front and back in test and detect XRPD respectively.Drawing for two kinds of crystal forms is moist As a result as shown in table 6 with XRPD characterization result.The DVS figure of crystal form I is as shown in figure 8, draw XRPD before and after moist test in the present invention Comparison diagram as shown in Figure 9 (crystal form is constant).The DVS figure such as Figure 10 of the monosuccinic acid salt anhydrous crystal forms of patent CN103201275 Shown, the comparison diagram for drawing moist test front and back XRPD is as shown in figure 11, and the following figure is the XRPD figure of anhydrous crystal forms starting, and upper figure is XRPD after DVS schemes (crystal form change).

Table 6

The result shows that crystal form will not change crystal form I of the invention under high humidity conditions, and in patent CN103201275 Crystal transfer easily occurs under high humidity conditions for monosuccinic acid salt anhydrous crystal forms.

Claims (7)

1. a kind of hemisuccinic acid salt crystal form A of formula (I) compound:

It is characterized in that, its X-ray powder diffraction figure 2theta value be 23.9 ° ± 0.2 °, 20.0 ° ± 0.2 °, 22.1 ° ± At 0.2 °, 22.0 ° ± 0.2 °, 21.3 ° ± 0.2 °, 13.0 ° ± 0.2 °, 4.7 ° ± 0.2 °, 14.2 ° ± 0.2 °, 26.2 ° ± 0.2 ° With characteristic peak.

2. formula (I) compound hemisuccinic acid salt crystal form A according to claim 1, which is characterized in that its x-ray powder spreads out It is substantially consistent with Fig. 1 to penetrate figure.

3. a kind of method for the hemisuccinic acid salt crystal form A for preparing formula described in claim 1 to 2 any one (I) compound, It is characterized in that, including formula (I) compound reacts in alcohols, alkyl nitrile, ether solvent with succinic acid, stirring and crystallizing obtains It arrives.

4. the alkyl nitrile solvents are acetonitrile, described according to the method described in claim 3, the alcohols solvent is ethyl alcohol Ether solvent is tetrahydrofuran.

5. according to the method described in claim 3, the formula (I) compound is arrived with the molar ratio of reacting of succinic acid between 1:0.4 1:1。

6. a kind of pharmaceutical composition contains according to claim 1 to half amber of formula described in 2 any one (I) compound Hydrochlorate crystal form A and pharmaceutically acceptable carrier.

7. being wanted according to claim 1 to the hemisuccinic acid salt crystal form A of formula described in 2 any one (I) compound or according to right Purposes of the pharmaceutical composition described in asking 6 in preparation treating cancer drug.