WO2022171138A1 - Crystalline form of nitrogen-containing heterocyclic compound, preparation method therefor and application thereof - Google Patents

Abstract

A crystalline form of a nitrogen-containing heterocyclic compound, a preparation method therefor and an application thereof. A crystalline form A of a compound represented by formula I, displaying a diffraction peak at 5.20±0.2°, 7.30±0.2°, 10.36±0.2°, 14.60±0.2°, 15.54±0.2°, 15.93±0.2°, 17.76±0.2°, 18.66±0.2°, 19.90±0.2°, 21.68±0.2°, and 22.64±0.2° in an X-ray powder diffraction spectrum represented by an angle of 2θ. The crystalline form has better stability. The pharmacokinetic property of the crystalline form A of the compound represented by formula I and a crystalline form C is better than that of an amorphous form.

Description

A kind of crystal form of nitrogen-containing heterocyclic compound, its preparation method and application

This application claims the priority of Chinese patent application 2021101854466 with a filing date of February 10, 2021. This application cites the full text of the above Chinese patent application.

technical field

The invention relates to a crystal form of a nitrogen-containing heterocyclic compound, a preparation method and application thereof.

Background technique

The epidermal growth factor receptor (EGFR, also known as ErbB or HER) family includes four receptor tyrosine kinases, namely EGFR (ErbB1 or HER1), ErbB2 (HER2), ErbB3 (HER3) and ErbB4 (HER4). Several investigators have demonstrated a role for EGFR and ErbB2 in cancer progression, and squamous cell carcinomas of the head, neck, and lung also express high levels of EGFR. ErbB2 overexpression occurs in 30% of all breast cancers and is also associated with other human cancers such as colon, ovary, bladder, stomach, esophagus, lung, uterine and prostate cancers. ErbB2 overexpression is also associated with poor prognosis in other cancers, including metastasis and early recurrence.

Chinese patent CN107141293A discloses a nitrogen-containing heterocyclic compound whose chemical name is N ⁴ -(4-([1,2,4]-triazolo[4,3-c]pyrimidin-7-yloxy)- 3-methylphenyl)-N ⁶ -(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine, its molecular formula is C ₂₅ H ₂₃ N ₉ O ₂ , whose structural formula is shown in formula I:

The above compounds can treat diseases by selectively inhibiting ErbB2 receptor tyrosine kinase. Chinese patent CN107141293A discloses that the compound of formula I is an amorphous compound. Generally speaking, an amorphous pharmaceutical product has no regular crystal structure and often has defects, such as poor thermodynamic stability. Therefore, it is necessary to improve various properties of the above-mentioned compounds.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is that the stability of the amorphous form of the existing formula I compound is poor, and for this reason, the present invention provides a crystal form of a nitrogen-containing heterocyclic compound, its preparation method and application. The crystal form of the present invention has better stability.

The present invention provides a crystalline form A of the compound represented by formula I, whose X-ray powder diffraction pattern represented by 2θ angle is at 5.20±0.2°, 7.30±0.2°, 10.36±0.2°, 14.60±0.2°, 15.54° There are diffraction peaks at ±0.2°, 15.93±0.2°, 17.76±0.2°, 18.66±0.2°, 19.90±0.2°, 21.68±0.2° and 22.64±0.2°;

In some embodiments of the present invention, preferably, the X-ray powder diffraction pattern represented by the 2θ angle of the crystal form A is further 16.37±0.2°, 16.95±0.2°, 18.30±0.2°, 19.16±0.2° , 19.73±0.2°, 20.76±0.2°, 22.04±0.2°, 22.81±0.2°, 23.97±0.2°, 24.54±0.2°, 24.91±0.2° and 26.38±0.2° have diffraction peaks at one or more places .

In some embodiments of the present invention, preferably, the X-ray powder diffraction pattern represented by the 2θ angle of the crystal form A is 11.56±0.2°, 12.12±0.2°, 13.18±0.2°, 15.27±0.2° , 20.54±0.2°, 21.27±0.2°, 23.02±0.2°, 23.22±0.2°, 23.64±0.2°, 25.69±0.2°, 26.01±0.2°, 27.53±0.2°, 28.13±0.2°, 28.64±0.2° , 28.97±0.2°, 30.37±0.2°, 32.31±0.2°, 33.69±0.2°, 34.60±0.2°, 35.36±0.2°, 35.94±0.2° and 37.96±0.2° have diffraction peaks at one or more places .

The X-ray powder diffraction pattern of the crystal form A represented by the 2θ angle, the X-ray powder diffraction pattern represented by the 2θ angle also has diffraction peaks at the diffraction angles as shown in Table 1:

Table 1

Numbering	Diffraction angle 2θ(±0.2°)
1	5.20
2	7.30
3	10.36
4	11.56
5	12.12
6	13.18
7	14.60
8	15.27
9	15.54
10	15.93

11	16.37
12	16.95
13	17.76
14	18.30
15	18.66
16	19.16
17	19.73
18	19.90
19	20.54
20	20.76
twenty one	21.27
twenty two	21.68
twenty three	22.04
twenty four	22.64
25	22.81
26	23.02
27	23.22
28	23.64
29	23.97
30	24.54
31	24.91
32	25.69
33	26.01
34	26.38
35	27.53
36	28.13
37	28.64
38	28.97
39	30.37
40	32.31

41	33.69
42	34.60
43	35.36
44	35.94
45	37.96

.

In some embodiments of the present invention, in the X-ray powder diffraction pattern of the crystal form A represented by 2θ angle, the diffraction peak, d value and peak height percentage can be shown in Table 2:

Table 2

Numbering	Diffraction angle 2θ(±0.2°)	d value	Relative Strength%
1	5.20	17.01	48.01
2	7.30	12.11	29.62
3	10.36	8.54	35.04
4	11.56	7.66	11.33
5	12.12	7.30	14.34
6	13.18	6.72	5.19
7	14.60	6.07	36.28
8	15.27	5.80	11.98
9	15.54	5.70	100.00
10	15.93	5.56	33.59
11	16.37	5.42	20.56
12	16.95	5.23	21.76
13	17.76	4.99	37.81
14	18.30	4.85	21.22
15	18.66	4.76	41.19
16	19.16	4.63	24.83
17	19.73	4.50	17.98
18	19.90	4.46	30.97
19	20.54	4.32	6.97
20	20.76	4.28	17.10
twenty one	21.27	4.18	10.59

twenty two	21.68	4.10	26.45
twenty three	22.04	4.03	17.56
twenty four	22.64	3.93	26.29
25	22.81	3.90	20.81
26	23.02	3.86	9.84
27	23.22	3.83	6.82
28	23.64	3.76	3.52
29	23.97	3.71	16.14
30	24.54	3.63	13.27
31	24.91	3.57	19.49
32	25.69	3.47	2.82
33	26.01	3.42	9.75
34	26.38	3.38	14.09
35	27.53	3.24	7.63
36	28.13	3.17	2.14
37	28.64	3.12	2.76
38	28.97	3.08	4.29
39	30.37	2.94	1.59
40	32.31	2.77	1.68
41	33.69	2.66	7.30
42	34.60	2.59	1.83
43	35.36	2.54	2.67
44	35.94	2.50	0.65
45	37.96	2.37	2.40

.

In some embodiments of the present invention, the XRPD pattern of the crystal form A is substantially as shown in FIG. 1 .

In some embodiments of the present invention, the crystal form A has a weight loss of ≤0.40% at a temperature range of 35°C to 150°C; preferably, the crystal form A has a weight loss of about 0.40% at 150°C.

In some embodiments of the present invention, the thermogravimetric analysis curve of the crystal form A is substantially as shown in FIG. 4 .

In some embodiments of the present invention, the thermogravimetric analysis curve of the crystal form A has an endothermic peak at 272.9±5°C.

In some embodiments of the present invention, the differential scanning calorimetry of the crystal form A is substantially as shown in FIG. 7 .

In some embodiments of the present invention, the hygroscopic weight gain of the crystal form A at 80% RH is 0.27%; preferably, the dynamic moisture adsorption pattern of the crystal form A is basically as shown in FIG. 10 .

In some embodiments of the present invention, the X-ray powder diffraction pattern is measured using Cu-Kα radiation lines.

The present invention provides a crystal form B of the compound represented by formula I, whose X-ray powder diffraction pattern represented by 2θ angle is at 9.92±0.2°, 10.45±0.2°, 10.81±0.2°, 15.71±0.2°, 16.32° There are diffraction peaks at ±0.2°, 17.01±0.2°, 20.93±0.2° and 22.31±0.2°;

In some embodiments of the present invention, preferably, the X-ray powder diffraction pattern of the crystal form B at 2θ angle is further 5.36±0.2°, 13.29±0.2°, 18.25±0.2°, 18.71±0.2° and One or more diffraction peaks at 25.01±0.2°.

In some embodiments of the present invention, preferably, in the X-ray powder diffraction pattern of the crystal form B represented by 2θ angle, its diffraction peak, d value and peak height percentage can also be as shown in Table 3:

table 3

Numbering	Diffraction angle 2θ(±0.2°)	d value	Relative Strength%
1	5.36	16.47	10.12
2	9.92	8.92	46.98
3	10.45	8.47	43.41
4	10.81	8.19	100.00
5	13.29	6.66	5.05
6	15.71	5.64	19.38
7	16.32	5.43	27.02
8	17.01	5.21	14.06
9	18.25	4.86	3.25
10	18.71	4.74	9.91
11	20.93	4.24	12.61
12	22.31	3.99	15.32
13	25.01	3.56	6.87

.

In some embodiments of the present invention, the XRPD pattern of the crystal form B is substantially as shown in FIG. 2 .

In some embodiments of the present invention, the weight loss of the crystal form B is ≤4.0% in the temperature range of 36.4°C to 160°C; preferably, the weight loss of the crystal form B is about 3.98% at 160°C.

In some embodiments of the present invention, the thermogravimetric analysis curve of the crystal form B is substantially as shown in FIG. 5 .

In some embodiments of the present invention, the thermogravimetric analysis curve of the crystal form B has endothermic peaks at 66.3±5°C and 278.0±5°C, and an exothermic peak at 180.3°C±5°C.

In some embodiments of the present invention, the differential scanning calorimetry of the crystal form B is substantially as shown in FIG. 8 .

In some embodiments of the present invention, the X-ray powder diffraction pattern is measured using Cu-Kα radiation lines.

The present invention provides a crystal form C of the compound represented by formula I, whose X-ray powder diffraction pattern represented by 2θ angle is at 7.61±0.2°, 11.28±0.2°, 13.82±0.2°, 16.71±0.2°, 20.12° There are diffraction peaks at ±0.2° and 22.30±0.2°;

In some embodiments of the present invention, preferably, the X-ray powder diffraction pattern of the crystal form C expressed at 2θ angle is further 15.25±0.2°, 23.54±0.2°, 25.01±0.2° and 25.89±0.2° There are diffraction peaks at one or more of them.

The present invention provides a crystalline form C of the compound represented by formula I, which is represented by X-ray powder diffraction at 2θ angle

Figure at 7.61±0.2°, 11.28±0.2°, 13.82±0.2°, 15.25±0.2°, 16.71±0.2°, 20.12±0.2°,

There are diffraction peaks at 22.30±0.2°, 23.54±0.2°, 25.01±0.2° and 25.89±0.2°;

In some embodiments of the present invention, preferably, the X-ray powder diffraction pattern represented by the 2θ angle of the crystal form C is further 9.38±0.2°, 10.65±0.2°, 12.87±0.2°, 15.71±0.2° , 17.98±0.2°, 18.79±0.2°, 21.47±0.2°, 27.25±0.2°, 28.10±0.2°, 30.83±0.2°, 32.31±0.2° and 33.93±0.2° have diffraction peaks at one or more places .

In some embodiments of the present invention, more preferably, the X-ray powder diffraction pattern of the crystal form C represented by the 2θ angle is at the diffraction angle as shown in Table 4. There are diffraction peaks at:

Table 4

Numbering	Diffraction angle 2θ(±0.2°)
1	7.61
2	9.38
3	10.65
4	11.28
5	12.87
6	13.82
7	15.25
8	15.71
9	16.71
10	17.98
11	18.79
12	20.12
13	21.47
14	22.30
15	23.54
16	25.01
17	25.89
18	27.25
19	28.10
20	30.83
twenty one	32.31
twenty two	33.93

.

In some embodiments of the present invention, preferably, in the X-ray powder diffraction pattern of the crystal form C represented by 2θ angle, its diffraction peak, d value and peak height percentage can be as shown in Table 5:

table 5

Numbering	Diffraction angle 2θ(±0.2°)	d value	Relative Strength%
1	7.61	11.62	15.84
2	9.38	9.43	3.49
3	10.65	8.31	5.64

4	11.28	7.84	100.00
5	12.87	6.88	4.88
6	13.82	6.41	12.61
7	15.25	5.81	8.25
8	15.71	5.64	4.42
9	16.71	5.31	15.21
10	17.98	4.93	3.19
11	18.79	4.72	1.54
12	20.12	4.41	35.66
13	21.47	4.14	3.38
14	22.30	3.99	34.73
15	23.54	3.78	9.00
16	25.01	3.56	8.39
17	25.89	3.44	7.35
18	27.25	3.27	3.49
19	28.10	3.18	5.98
20	30.83	2.90	2.21
twenty one	32.31	2.77	0.99
twenty two	33.93	2.64	0.82

In some embodiments of the present invention, the XRPD pattern of the crystal form C is substantially as shown in FIG. 3 .

In some embodiments of the present invention, the weight loss of the crystal form C in the temperature range of 29.0°C to 150°C is less than or equal to 0.90%; preferably, the weight loss of the crystal form C at 150°C is about 0.90%.

In some embodiments of the present invention, the thermogravimetric analysis curve of the crystal form C is substantially as shown in FIG. 6 .

In some embodiments of the present invention, the thermogravimetric analysis curve of the crystal form C has an endothermic peak at 289.2±5°C and an exothermic peak at 244.5±5°C.

In some embodiments of the present invention, the differential scanning calorimetry of the crystal form C is substantially as shown in FIG. 9 .

In some embodiments of the present invention, the X-ray powder diffraction pattern is measured using Cu-Kα radiation lines.

The present invention also provides a method for preparing the aforementioned crystal form A of the compound represented by formula I, which includes Scheme 1 or Scheme 2;

The described scheme 1 comprises the following steps: the described compound shown in formula I is slurried and crystallized in methanol, and the solid is collected to obtain the described crystal form A of the compound shown in formula I, the described methanol and the described The volume-to-mass ratio of the compound shown in formula I is 10-50 mL/g;

Described scheme 2 comprises the steps: the solution of described compound shown in formula I separates out solid by cooling down and/or the natural volatilization of solvent, collects solid and obtains described crystal form A of compound shown in formula I, described The solvent of the solution is a mixed solvent of dichloromethane and methanol; the volume ratio of the dichloromethane and methanol is 1:(1～4); the mixed solvent and the compound shown in the formula I The volume-to-mass ratio is 20-200 mL/g.

In some embodiments of the present invention, the scheme 1 and scheme 2 further include drying.

In some embodiments of the present invention, the drying temperature may be 45±5°C.

In some embodiments of the present invention, the beating method is a conventional beating method in the field, such as stirring.

In some embodiments of the present invention, the solution of the compound represented by formula I is obtained by stirring at room temperature or heating under reflux.

In some embodiments of the present invention, preferably, in the scheme 1, the volume-to-mass ratio of the mixed solvent to the compound represented by formula I is 20-30 mL/g; for example, 20 mL/g.

In some embodiments of the present invention, preferably, in the scheme 2, the volume-to-mass ratio of the mixed solvent to the compound represented by formula I may be 105 mL/g.

The present invention also provides a method for preparing the aforementioned crystal form B of the compound shown in formula I, which comprises the following steps: the solution of the compound shown in formula I is volatilized to separate out a solid, and the solid is collected to obtain the described For the crystal form B of the compound represented by formula I, the solvent in the solution is a mixed solvent of dichloromethane and methanol.

In some embodiments of the present invention, the volume ratio of the dichloromethane and methanol may be 83:1.

In some embodiments of the present invention, the volume-to-mass ratio of the mixed solvent to the compound represented by formula I is 0.7 mL/mg.

The present invention also provides a method for preparing the aforementioned crystal form C of the compound shown in formula I, which comprises the following steps: the compound shown in formula I is slurried and crystallized in tetrahydrofuran, and the solid is collected to obtain the The crystal form C of the compound represented by formula I; the volume-to-mass ratio of the tetrahydrofuran to the compound represented by formula I is 10-50 mL/g.

In some embodiments of the present invention, the preparation method further comprises vacuum drying.

In some embodiments of the present invention, the vacuum drying temperature may be 45±5°C.

In some embodiments of the present invention, preferably, the volume-to-mass ratio of the tetrahydrofuran to the compound represented by formula I is 10-30 mL/g, for example, 16 mL/g.

In some embodiments of the present invention, the beating method is a conventional beating method in the field, such as stirring.

The present invention also provides a pharmaceutical composition comprising substance X and at least one pharmaceutical excipient; the substance X is the aforementioned crystalline form A or C of the compound represented by formula I.

The present invention also provides a pharmaceutical composition comprising substance Y and at least one pharmaceutical excipient, the aforementioned crystal form B of the compound represented by formula I.

The selection of the pharmaceutical excipients varies due to the route of administration and the characteristics of the action, and can usually be the conventional fillers, diluents, binders, wetting agents, disintegrating agents, lubricants, emulsifiers, suspending agents in the field. agent, etc.

The pharmaceutical compositions can be administered orally, by injection (intravenous, intramuscular, subcutaneous and intracoronary), sublingually, buccally, rectally, urethraally, vaginally, nasally, by inhalation or topically, the preferred route is oral.

The present invention provides the use of the aforementioned crystalline form A or C of the compound represented by formula I in the preparation of a medicine or an "EGFR and/or ErbB2 receptor tyrosine kinase inhibitor", the medicine is used for inhibiting the EGFR and/or ErbB2 receptor tyrosine kinase-treated disease or ErbB2 (HER2)-positive advanced malignancy.

In some embodiments of the present invention, the "disease treated by inhibition of EGFR and/or ErbB2 receptor tyrosine kinase" is a disease treated by selective inhibition of ErbB2 receptor tyrosine kinase.

In some embodiments of the present invention, the "EGFR and/or ErbB2 receptor tyrosine kinase inhibitor" is a selective ErbB2 receptor tyrosine kinase inhibitor.

In some embodiments of the present invention, the disease to be treated by selectively inhibiting ErbB2 receptor tyrosine kinase is breast cancer or gastric cancer.

In some embodiments of the present invention, the disease of the ErbB2 (HER2) positive advanced malignant tumor is breast cancer.

The present invention provides a use of the aforementioned crystalline form B of the compound represented by formula I in the preparation of a drug or an "EGFR and/or ErbB2 receptor tyrosine kinase inhibitor" for inhibiting EGFR and/or ErbB2 receptor tyrosine kinase inhibitors. and/or ErbB2 receptor tyrosine kinase-treated disease or ErbB2 (HER2)-positive advanced malignancy.

In some embodiments of the present invention, the "disease treated by inhibition of EGFR and/or ErbB2 receptor tyrosine kinase" is a disease treated by selective inhibition of ErbB2 receptor tyrosine kinase.

In some embodiments of the present invention, the "EGFR and/or ErbB2 receptor tyrosine kinase inhibitor" is a selective ErbB2 receptor tyrosine kinase inhibitor.

In some embodiments of the present invention, the disease to be treated by selectively inhibiting ErbB2 receptor tyrosine kinase is breast cancer or gastric cancer.

In some embodiments of the present invention, the disease of the ErbB2 (HER2) positive advanced malignant tumor is breast cancer.

On the basis of not violating common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

The reagents and raw materials used in the present invention are all commercially available.

The positive progressive effect of the present invention is:

The present invention provides a crystal form A, B or C of the compound represented by formula I. Compared with the amorphous form described in Example 4 of CN107141293A, the crystal form of the present invention has more stable thermal stability properties. The pharmacokinetic properties of Form A and Form C are better than those of the amorphous form.

Description of drawings

Fig. 1 is the X-ray powder diffraction pattern of the crystal form A obtained in Example 1;

Fig. 2 is the X-ray powder diffractogram of obtained crystal form B in embodiment 2;

Fig. 3 is the X-ray powder diffractogram of the obtained crystal form C in embodiment 3;

Fig. 4 is the thermogravimetric analysis diagram of obtained crystal form A in embodiment 1;

Fig. 5 is the thermogravimetric analysis diagram of obtained crystal form B in embodiment 2;

Fig. 6 is the thermogravimetric analysis diagram of obtained crystal form C in embodiment 3;

Fig. 7 is the differential scanning calorimetry of the crystal form A obtained in Example 1;

Fig. 8 is the differential scanning calorimeter of the crystal form B obtained in Example 2;

Fig. 9 is the differential scanning calorimetry of the crystal form C obtained in Example 3;

Fig. 10 is the hygroscopicity test (DVS) diagram of the obtained crystal form A in Example 1;

Fig. 11 is the X-ray powder diffraction comparison diagram before and after the obtained crystal form A moisture attracting property test in Example 1;

Fig. 12 is the change diagram of crystal form B heating X-ray powder diffraction pattern in Effect Example 1;

Fig. 13 is the change diagram of crystal form C heating X-ray powder diffractogram in Effect Example 1;

Figure 14 is the X-ray powder diffraction pattern of the amorphous compound I prepared according to the method described in Example 4 of Chinese Patent CN107141293A.

Detailed ways

The present invention is further described below by way of examples, but the present invention is not limited to the scope of the described examples. The experimental methods that do not specify specific conditions in the following examples are selected according to conventional methods and conditions, or according to the product description.

Instruments and methods used to collect data:

The X-ray powder diffraction patterns described in this application were collected on a PANalytical Empyrean X-ray powder diffractometer and a PANalytical X'Pert3 X-ray powder diffractometer.

The method parameters for Empyrean-type X-ray powder diffraction are as follows:

X-ray type: Cu, Kα

1.540598;

1.544426

Kα2/Kα1 intensity ratio: 0.50

Voltage: 45 thousand volts (kV)

Current: 40 milliamps (mA)

Divergence slit: automatic

Scan Mode: Continuous

Scanning range: from 3.0 to 40.0 degrees

Scan time per step: 17.780 seconds

Step size: 0.0167 degrees

The method parameters of PANalytical X'Pert3 X-ray powder diffraction are as follows:

X-ray type: Cu, Kα

1.540598;

1.544426

Kα2/Kα1 intensity ratio: 0.50

Voltage: 45 thousand volts (kV)

Current: 40 milliamps (mA)

Divergence slit: 1/16 degree

Scan Mode: Continuous

Scanning range: from 3.0 to 40.0 degrees

Scan time per step: 46.665 seconds

Step size: 0.0263 degrees

The differential scanning calorimetry (DSC) data described in this application were collected from TA Instruments Q200 and TA Instruments Q2000 differential scanning calorimeters, the instrument control software was Q Series, and the analysis software was Universal Analysis. Usually 1-10 mg of the sample is placed in an aluminum crucible with a lid (unless otherwise specified), and the sample is raised from room temperature to 300 °C at a heating rate of 10 °C/min under the protection of 50 mL/min of dry _N2 , At the same time, the TA software recorded the heat change of the sample during the heating process. In this application, melting points are reported as onset temperatures.

The thermogravimetric analysis (TGA) data described in this application are collected from TA Instruments Q500 and TA Instruments Q5000 thermogravimetric analyzers, the instrument control software is Q Series, and the analysis software is Universal Analysis. Usually 2-15mg of the sample is placed in a platinum crucible, and the sample is raised from room temperature to 400°C at a heating rate of 10°C/min under the protection of 50mL/min dry _N2 by means of segmented high-resolution detection. At the same time, the TA software recorded the weight change of the sample during the heating process.

The dynamic moisture adsorption diagrams described in this application were collected on Intrinsic-type and Intrinsic Plus-type dynamic moisture adsorption instruments of SMS company. The method parameters of the dynamic moisture adsorption test of the present invention are as follows:

Temperature: 25℃

Protective gas and flow: N ₂ , 200 ml/min

dm/dt: 0.002%/min

Minimum dm/dt equilibration time: 10 minutes

Maximum Equilibration Time: 180 minutes

Relative humidity range: 0%RH-95%RH-0%RH

Relative humidity gradient: 10% (0%RH-90%RH-0%RH), 5% (90%RH-95%RH and 95%RH-90%RH)

The amorphous sample of Compound I described in the following examples was prepared by the method described in Example 4 of CN107141293A, and its XRPD pattern is shown in FIG. 14 .

Example 1 Preparation of Compound I Crystal Form A

Amorphous sample 5g, methanol 100mL, stirring at 25°C for 18h for crystallization, suction filtration, vacuum drying at 45±5°C to obtain a solid sample, which is compound I crystal form A with a purity of 99.8%.

Example 2 Preparation of Compound I Crystal Form A

Sampling 0.4g amorphous sample, dichloromethane/methanol (1:4, v/v) 42ml, reflux to dissolve clear, open to stand for volatilization to obtain a solid, suction filtration, 45 ± 5 ℃ vacuum drying drying, that is Compound I, crystal form A, has a purity of 99.57%.

After testing, the X-ray powder diffraction data of the solids obtained in Example 1 and Example 2 are shown in Table 6, the XRPD diagram is shown in Figure 1, the TGA diagram is shown in Figure 4, and the DSC diagram is shown in Figure 7 , the results show that the obtained solid product is the crystal form A described in the application. TGA data shows that the crystal sample loses about 0.40% weight when heated to 150°C, and there is a single melting endothermic peak at 272.9°C (peak temperature) in DSC.

About 20 mg of crystal form A was taken, and its hygroscopicity was tested by dynamic moisture adsorption (DVS) instrument. The experimental results are shown in Table 7. The DVS diagram of the wettability test is shown in Figure 10, and the XRPD comparison diagram before and after the sample test is shown in Figure 11.

Table 6

Numbering	Diffraction angle 2θ(±0.2°)	d value	Relative Strength%
1	5.20	17.01	48.01
2	7.30	12.11	29.62
3	10.36	8.54	35.04
4	11.56	7.66	11.33
5	12.12	7.30	14.34
6	13.18	6.72	5.19
7	14.60	6.07	36.28

8	15.27	5.80	11.98
9	15.54	5.70	100.00
10	15.93	5.56	33.59
11	16.37	5.42	20.56
12	16.95	5.23	21.76
13	17.76	4.99	37.81
14	18.30	4.85	21.22
15	18.66	4.76	41.19
16	19.16	4.63	24.83
17	19.73	4.50	17.98
18	19.90	4.46	30.97
19	20.54	4.32	6.97
20	20.76	4.28	17.10
twenty one	21.27	4.18	10.59
twenty two	21.68	4.10	26.45
twenty three	22.04	4.03	17.56
twenty four	22.64	3.93	26.29
25	22.81	3.90	20.81
26	23.02	3.86	9.84
27	23.22	3.83	6.82
28	23.64	3.76	3.52
29	23.97	3.71	16.14
30	24.54	3.63	13.27
31	24.91	3.57	19.49
32	25.69	3.47	2.82
33	26.01	3.42	9.75
34	26.38	3.38	14.09
35	27.53	3.24	7.63
36	28.13	3.17	2.14
37	28.64	3.12	2.76

38	28.97	3.08	4.29
39	30.37	2.94	1.59
40	32.31	2.77	1.68
41	33.69	2.66	7.30
42	34.60	2.59	1.83
43	35.36	2.54	2.67
44	35.94	2.50	0.65
45	37.96	2.37	2.40

Table 7 Hygroscopicity test of Form A

About the description of hygroscopicity characteristics and the definition of hygroscopicity weight gain (Chinese Pharmacopoeia 2010 Edition Appendix XIX J Guidelines for the hygroscopicity test of drugs, experimental conditions: 25℃±1℃, 80% relative humidity):

Deliquescence: Absorbs sufficient water to form a liquid

Extremely hygroscopic: wet weight gain is not less than 15%

Moisture: Moisture gain is less than 15% but not less than 2%

Slightly hygroscopic: wet weight gain is less than 2% but not less than 0.2%

No or almost no hygroscopicity: hygroscopic weight gain is less than 0.2%.

Example 3 Preparation of Compound I Crystal Form B

Weigh about 15 mg of amorphous sample into a 20 mL glass vial, add 0.5 mL of dichloromethane/methanol (3:1, v/v) to dissolve the sample, filter the resulting solution into another 20 mL glass vial, add 0.5 mL of dichloromethane/methanol (3:1, v/v) to the resulting clear solution 10 mL of dichloromethane was added, and the obtained sample was transferred to room temperature for volatilization to obtain a solid, which was Compound I Crystal Form B.

After testing, the X-ray powder diffraction data of the solid obtained in Example 3 is shown in Table 8, its XRPD diagram is shown in Figure 2, its TGA diagram is shown in Figure 5, and its DSC diagram is shown in Figure 8, the results show that the obtained The solid product is the crystal form B described in this application. TGA data shows that the sample of this crystal form loses about 3.98% in weight when heated to 160°C, and there are endothermic peaks at 66.3°C (peak temperature) and 278.0°C (peak temperature) in DSC, There is an exothermic peak at 180.3°C (peak temperature).

Table 8

Numbering

Diffraction angle 2θ(±0.2°)

d value

Relative Strength%

1	5.36	16.47	10.12
2	9.92	8.92	46.98
3	10.45	8.47	43.41
4	10.81	8.19	100.00
5	13.29	6.66	5.05
6	15.71	5.64	19.38
7	16.32	5.43	27.02
8	17.01	5.21	14.06
9	18.25	4.86	3.25
10	18.71	4.74	9.91
11	20.93	4.24	12.61
12	22.31	3.99	15.32
13	25.01	3.56	6.87

Example 4 Preparation of Compound I Crystal Form C

Take 2.5 g of amorphous sample, add 40 ml of tetrahydrofuran, stir at room temperature for 3 h to obtain a solid, suction filtration, and vacuum dry at 45±5 °C to obtain a solid, which is compound I crystal form C with a purity of 99.78%.

After testing, the X-ray powder diffraction data of the solid obtained in this example is shown in Table 9, its XRPD diagram is shown in Figure 3, its TGA diagram is shown in Figure 6, and its DSC diagram is shown in Figure 9, the results show that the obtained The solid product is the crystal form C described in this application. TGA data shows that the sample of this crystal form loses about 0.90% when heated to 150°C, and there is an exothermic peak at 244.5°C (peak temperature) in DSC, and an exothermic peak at 289.2°C (peak temperature) There is an endothermic peak.

Table 9

Numbering	Diffraction angle 2θ(±0.2°)	d value	Relative Strength%
1	7.61	11.62	15.84
2	9.38	9.43	3.49
3	10.65	8.31	5.64
4	11.28	7.84	100.00
5	12.87	6.88	4.88
6	13.82	6.41	12.61
7	15.25	5.81	8.25
8	15.71	5.64	4.42
9	16.71	5.31	15.21

10	17.98	4.93	3.19
11	18.79	4.72	1.54
12	20.12	4.41	35.66
13	21.47	4.14	3.38
14	22.30	3.99	34.73
15	23.54	3.78	9.00
16	25.01	3.56	8.39
17	25.89	3.44	7.35
18	27.25	3.27	3.49
19	28.10	3.18	5.98
20	30.83	2.90	2.21
twenty one	32.31	2.77	0.99
twenty two	33.93	2.64	0.82

.

Effect Example 1: Crystal Form Conversion Relationship

As shown in Figure 12, the crystal form B was heated to 210 °C and transformed into the crystal form A (the crystal form B was heated to 210 °C by conventional methods, and then the crystal form changes were detected). B is stable.

As shown in Figure 13, the crystal form C is transformed into the crystal form A after heating to 260 °C. According to the Burger-Ramberger Rules, it shows that the crystal form A is more stable than C.

Conclusion: Form A is more thermodynamically stable than forms B and C.

Effect Example 2: Table 10 shows the results of the solid-state stability test.

Table 10

Conclusion: Amorphous and Form A were evaluated by placing open for one week at 25°C/60%RH and 25°C/60%RH, and Form A sealed at 80°C for 24 hours. The results show that: no The purity of the shape decreases under the test conditions, and the crystal form A has better physical and chemical stability under the above test conditions.

Effect Example 3: Comparison of in vivo absorption in rats after administration of different crystal forms and amorphous forms

SD rats (provided by Shanghai Sipple Bikai Laboratory Animal Co., Ltd., certificate number: 2008001669476) were divided into groups of 5, and were given different crystal forms and amorphous forms (see Table 10) by gavage respectively. Before and 5, 15, 30, 60, 90, 120, 240, 360, 480, 600, and 1440 min after administration, 0.4 mL of blood was collected from the fundus venous plexus of rats. The blood samples were centrifuged at 8000 rpm for 5 min, the upper plasma was separated, 50 μL of plasma sample was added, 300 μL of acetonitrile (Propranolol, 25 ng/ml) containing internal standard was added to precipitate the protein, vortexed for 10 min, 6000 g, 4 °C for 20 min, 20 μL of supernatant was taken and 80 μL of ultrapure water was added After dilution, 80 μL of supernatant was taken by centrifugation and injected into 96-well plate, and the plasma drug concentration was obtained by LC/MS/MS detection, and then the corresponding pharmacokinetic parameters were calculated, (CMC-Na is sodium carboxymethyl cellulose, HPMC is hydroxypropyl methylcellulose) shown in Table 12.

Table 11 Animal grouping and administration

Table 12 Pharmacokinetic parameters after oral administration of samples of different crystal forms

Conclusion: In this experiment, the samples of crystal form A and crystal form C were suspended with 0.5% HPMC and 0.5% CMC-Na, and the amorphous form was suspended with 0.5% CMC-Na, and the rats were given intragastrically at a dose of 15 mg/kg. The results showed that the pharmacokinetic properties of crystal form A and crystal form C were better than those of amorphous form.

Claims (13)

1. A crystal form A of the compound represented by formula I, characterized in that its X-ray powder diffraction pattern represented by 2θ angle is at 5.20±0.2°, 7.30±0.2°, 10.36±0.2°, 14.60±0.2°, There are diffraction peaks at 15.54±0.2°, 15.93±0.2°, 17.76±0.2°, 18.66±0.2°, 19.90±0.2°, 21.68±0.2° and 22.64±0.2°;

   
2. The crystal form A of the compound represented by formula I according to claim 1, characterized in that, the X-ray powder diffraction pattern represented by the 2θ angle of the crystal form A is further 16.37±0.2°, 16.95±0.2° degrees There are diffraction peaks at one or more places in °;

   And/or, the crystal form A has a weight loss of ≤0.40% in the temperature range of 35°C to 150°C;

   And/or, the thermogravimetric analysis curve of the crystal form A has an endothermic peak at 272.9±5°C;

   And/or, the hygroscopic weight gain of the crystal form A at 80% RH is 0.27%;

   And/or, the X-ray powder diffraction pattern is measured using Cu-Kα radiation lines.
3. The crystal form A of the compound represented by formula I according to claim 2, wherein the X-ray powder diffraction pattern of the crystal form A expressed by 2θ angle is further at 11.56±0.2°, 12.12±0.2° degrees degrees There are diffraction peaks at one or more places in °; preferably, the XRPD spectrum of the crystal form A is basically as shown in Figure 1;

   And/or, the crystal form A loses 0.40% weight at 150°C; preferably, the thermogravimetric analysis curve of the crystal form A is basically as shown in Figure 4;

   And/or, the differential scanning calorimetry of the crystal form A is basically as shown in Figure 7;

   And/or, the dynamic moisture adsorption spectrum of the crystal form A is basically as shown in FIG. 10 .
4. A preparation method of the crystal form A of the compound shown in formula I as described in any one of claims 1-3, it is characterized in that, it is scheme 1 or scheme 2,

   The described scheme 1 comprises the following steps: the described compound shown in formula I is slurried and crystallized in methanol, and the solid is collected to obtain the described crystal form A of the compound shown in formula I, the described methanol and the described The volume-to-mass ratio of the compound shown in formula I is 10-50 mL/g;

   Described scheme 2 comprises the steps: the solution of described compound shown in formula I separates out solid by cooling down and/or the natural volatilization of solvent, collects solid and obtains described crystal form A of compound shown in formula I, described The solvent of the solution is a mixed solvent of dichloromethane and methanol; the volume ratio of the dichloromethane and methanol is 1:(1～4); the mixed solvent and the compound shown in the formula I The volume-to-mass ratio is 20-200 mL/g.
5. The method for preparing the crystal form A of the compound represented by formula I according to claim 4, wherein the scheme 1 and scheme 2 further comprise drying; preferably, the drying temperature is 45 ℃ ±5℃;

   And/or, in described scheme 2, the volume ratio mass body of described mixed solvent and described compound shown in formula I is 105mL/g;

   And/or, the method of described beating is stirring;

   And/or, the described solution of compound shown in formula I is obtained by stirring at normal temperature or heating under reflux;

   And/or, in the scheme 1, the volume-to-mass ratio of the mixed solvent to the compound represented by formula I is 20-30 mL/g; for example, 20 mL/g.
6. A crystalline form C of a compound represented by formula I, whose X-ray powder diffraction pattern represented by 2θ angle is at 7.61±0.2°, 11.28±0.2°, 13.82±0.2°, 16.71±0.2°, 20.12±0.2° and diffraction peaks at 22.30±0.2°;

   
7. The crystal form C of the compound of formula I according to claim 6, characterized in that, the X-ray powder diffraction pattern represented by the 2θ angle of the crystal form C is further at 15.25±0.2°, 23.54±0.2° There are diffraction peaks at one or more of °, 25.01±0.2° and 25.89±0.2°.
8. A crystal form C of the compound represented by formula I, characterized in that its X-ray powder diffraction pattern represented by 2θ angle is at 7.61±0.2°, 11.28±0.2°, 13.82±0.2°, 15.25±0.2°, 16.71±0.2°, 20.12±0.2°,

   There are diffraction peaks at 22.30±0.2°, 23.54±0.2°, 25.01±0.2° and 25.89±0.2°;

   
9. The crystal form C of the compound represented by formula I according to claim 8, characterized in that, the X-ray powder diffraction pattern represented by the 2θ angle of the crystal form C is further 9.38±0.2°, 10.65±0.2° degrees There are diffraction peaks at one or more places in °;

   And/or, the weight loss of the crystal form C in the temperature range of 29.0°C to 150°C is less than or equal to 0.90%; preferably, the weight loss of the crystal form C at 150°C is about 0.90%;

   And/or, the thermogravimetric analysis curve of the crystal form C has an endothermic peak at 289.2±5°C and an exothermic peak at 244.5±5°C;

   And/or, the X-ray powder diffraction pattern is measured using Cu-Kα radiation lines.
10. The crystal form C of the compound of formula I according to claim 9, wherein the XRPD spectrum of the crystal form C is substantially as shown in Figure 3;

    And/or, the thermogravimetric analysis curve atlas of described crystal form C is basically as shown in Figure 6;

    And/or, the differential scanning calorimetry of the crystal form C is basically as shown in FIG. 9 .
11. A preparation method of the crystal form C of the compound shown in formula I as described in any one of claims 6-10, it is characterized in that, it comprises the steps: described compound shown in formula I in tetrahydrofuran Slurry crystallization in the middle, collect the solid to obtain the crystal form C of the compound shown in formula I; the volume-to-mass ratio of the tetrahydrofuran and the compound shown in formula I is 10～50mL/g;

    Preferably, the preparation method further comprises vacuum drying; more preferably, the vacuum drying temperature is 45±5°C;

    And/or, the volume-to-mass ratio of the tetrahydrofuran to the compound shown in formula I is 10 to 30 mL/g, for example 16 mL/g;

    And/or, the method of beating is stirring.
12. A pharmaceutical composition is characterized in that, it comprises substance X and at least one pharmaceutical adjuvant; Described substance X is the crystal form of compound shown in formula I as described in any one of claim 1-3 A or the crystalline form C of the compound represented by formula I according to any one of claims 6-10.
13. A crystal form A of the compound shown in the formula I as described in any one of claims 1-3 or the crystal form C of the compound shown in the formula I as described in any one of claims 6-10 in Preparation of medicaments, use in "EGFR and/or ErbB2 receptor tyrosine kinase inhibitors" for treating diseases or ErbB2-positive advanced stages by inhibiting EGFR and/or ErbB2 receptor tyrosine kinases Malignant diseases;

    Preferably, the "disease treated by inhibiting EGFR and/or ErbB2 receptor tyrosine kinase" is a disease treated by selectively inhibiting ErbB2 receptor tyrosine kinase;

    And/or, the "EGFR and/or ErbB2 receptor tyrosine kinase inhibitor" is a selective ErbB2 receptor tyrosine kinase inhibitor;

    More preferably, the disease treated by selectively inhibiting ErbB2 receptor tyrosine kinase is breast cancer or gastric cancer;

    And/or, the ErbB2-positive advanced malignant tumor is breast cancer.

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